Thiazolopyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase

ABSTRACT

Thiazolopyrimidines of formula (I): wherein W represents a thiazole ring; R 1  and R 2  form, together with the N atom to which they are attached, a group of the following formula (IIa): in which A is a ring system; m is 0, 1 or 2; R is H or C 1 -C 6  alkyl; and R is an indole group which is unsubstituted or substituted; and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PD kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

FIELD OF THE INVENTION

The present invention relates to indolyl thiazolopyrimidine compoundsand to their use as inhibitors of phosphatidylinositol 3-kinase (PI3K).

BACKGROUND TO THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. In the late 1980s, a PI3 kinase (PI3K) was found to be anenzyme which phosphorylates the 3-position of the inositol ring ofphosphatidylinositol (D. Whitman et al. 1988, Nature, 332, 664).

PI3K was originally considered to be a single enzyme, but it has nowbeen clarified that a plurality of subtypes are present in PI3K. Eachsubtype has its own mechanism for regulating activity. Three majorclasses of PI3Ks have been identified on the basis of their in vitrosubstrate specificity (B. Vanhaesebroeck, 1997, Trend in Biol. Sci, 22,267). Substrates for class I PI3Ks are PI, PI 4-phosphate (PI4P) and PI4,5-biphosphate (I (4,5)P2). Class I PI3Ks are further divided into twogroups, class Ia and class Ib, in terms of their activation mechanism.Class Ia PI3Ks include PI3K p110α, p110β and p110δ subtypes, whichtransmit signals from tyrosine kinase-coupled receptors. Class Ib PI3Kincludes a p110γ subtype activated by a G protein-coupled receptor. PIand PI(4)P are known as substrates for class II PI3Ks. Class II PI3Ksinclude PI3K C2α, C2β and C2γ subtypes, which are characterized bycontaining C2 domains at the C terminus. The substrate for class IIIPI3Ks is PI only.

In the PI3K subtypes, the class Ia subtype has been most extensivelyinvestigated to date. The three subtypes of class Ia are heterodimers ofa catalytic 110 kDa subunit and regulatory subunits of 85 kDa or 55 kDa.The regulatory subunits contain SH2 domains and bind to tyrosineresidues phosphorylated by growth factor receptors with a tyrosinekinase activity or oncogene products, thereby inducing the PI3K activityof the p110 catalytic subunit which phosphorylates its lipid substrate.Thus, the class Ia subtypes are considered to be associated with cellproliferation and carcinogenesis, immune disorders and conditionsinvolving inflammation.

WO 01/083456 describes a series of condensed heteroaryl derivativeswhich have activity as inhibitors of PI3 K and which suppress cancercell growth.

SUMMARY OF THE INVENTION

It has now been found that a series of novel thiazolopyrimidinecompounds have activity as inhibitors of PI3K. The compounds exhibitselectivity for the p1105 subtype of PI3 kinase, over both other classIa and class Ib PI3Ks. Accordingly, the present invention provides acompound which is a thiazolopyrimidine of formula (I):

wherein

W represents a thiazole ring;

R¹ and R² form, together with the N atom to which they are attached, agroup of the following formula (IIa):

in which A is selected from:

-   -   (a) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O, the ring being unsubstituted or substituted;    -   (b) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O, the ring being fused to a second ring selected from a 4-        to 7-membered saturated N-containing heterocyclic ring as        defined above, a 5- to 12-membered unsaturated heterocyclic        ring, a 5- to 7-membered saturated O-containing heterocyclic        ring, a 3- to 12-membered saturated carbocyclic ring and an        unsaturated 5- to 12-membered carbocyclic ring to form a        heteropolycyclic ring system, the heteropolycyclic ring system        being unsubstituted or substituted;    -   (c) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O and which further comprises, linking two constituent atoms        of the ring, a bridgehead group selected from (CR′₂)_(n)— and        (CR′₂), O—(CR′₂)_(s)— wherein each R′ is independently H or        C₁-C₆ alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the        remaining ring positions being unsubstituted or substituted; and    -   (d) a group of formula (IIb):

-   -    wherein ring B is a 4- to 7-membered saturated N-containing        heterocyclic ring which includes 0 or 1 additional heteroatoms        selected from N, S and O and ring B′ is a 3- to 12-membered        saturated carbocyclic ring, a 5- to 7-membered saturated        O-containing heterocyclic ring or a 4- to 7-membered saturated        N-containing heterocyclic ring as defined above, each of B and        B′ being unsubstituted or substituted;    -   or one of R¹ and R² is C₁-C₆ alkyl and the other of R¹ and R² is        selected from a 3- to 12-membered saturated carbocyclic group        which is unsubstituted or substituted, a 5- to 12-membered        unsaturated carbocyclic group which is unsubstituted or        substituted, a 5- to 12-membered unsaturated heterocyclic group        which is unsubstituted or substituted, a 4- to 12-membered        saturated heterocyclic group which is unsubstituted or        substituted and a C₁-C₆ alkyl group which is substituted by a        group selected from a 3- to 12-membered saturated carbocyclic        group which is unsubstituted or substituted, a 5- to 12-membered        unsaturated carbocyclic group which is unsubstituted or        substituted, a 5- to 12-membered unsaturated heterocyclic group        which is unsubstituted or substituted and a 4- to 12-membered        saturated heterocyclic group which is unsubstituted or        substituted;    -   m is 0, 1 or 2;    -   R³ is H or C₁-C₆ alkyl; and    -   R⁴ is an indole group which is unsubstituted or substituted;    -   or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “fused” indicates that two rings are joinedtogether by a common bond between two adjacent ring atoms. The term“spiro-fused” indicates that two rings are linked through a singlecommon carbon atom, The term “bridgehead” denotes a linking group, ofone or more atoms in length, which connects two non-adjacent ring atoms.In each of these three cases a polycyclic (typically a bicyclic)structure is the result.

When any group, ring, group, ring, substituent or moiety defined hereinis substituted, it is typically substituted by Z or R⁵ as defined below.

A C₁-C₆ alkyl group is linear or branched. A C₁-C₆ alkyl group istypically a C₁-C₄ alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl or tert-butyl group. A C₁-C₆ alkyl group isunsubstituted or substituted, typically by one or more groups Z or R⁵ asdefined below. Typically it is C₁-C₄ alkyl, for example methyl, ethyl,i-propyl, n-propyl, t-butyl, s-butyl or n-butyl.

Z is selected from H, unsubstituted C₁-C₆ alkyl, halo, —OR, —SR,—(C(R⁶)₂)_(q)R, —CH₂OR, —CF₃, -(halo)-C₁-C₆ alkyl,—(C(R⁶)₂)_(q)O-(halo)-C₁-C₆ alkyl, —CO₂R, —(C(R⁶)₂)_(q)CO₂R,—(C(R⁶)₂)_(q)COR, CF₂OH, CH(CF₃)OH, C(CF₃)₂OH, —(CH₂)_(q)OR,—(C(R⁶)₂)_(q)OR, —(CH₂)_(q)NR₂, —(C(R⁶)₂)_(q)NR₂, —C(O)N(R)₂,—(C(R⁶)₂)_(q)CONR₂—NR₂, —(C(R⁶)₂)_(q)NR₂, —(C(R⁶)₂)_(q)NRC(O)R,—(C(R⁶)₂)_(q)NRC(O)OR, —S(O)_(p)R, —S(O)_(p)N(R)₂,—(C(R⁶)₂)_(q)S(O)_(p)N(R)₂, —OC(O)R, —(C(R⁶)₂)_(q)OC(O)R, —OC(O)N(R)₂,—(C(R⁶)₂)_(q)OC(O)N(R)₂, —NRS(O)_(p)R, —(C(R⁶)₂)_(q)NRS(O)_(p)R,—NRC(O)N(R)₂, —(C(R⁶)₂)_(q)NRC(O)N(R)₂, CN, —NO₂, ═O, a 3- to12-membered saturated carbocyclic ring which is unsubstituted orsubstituted, a 5- to 12-membered unsaturated carbocyclic which isunsubstituted or substituted, a 5- to 12-membered unsaturatedheterocyclic group which is unsubstituted or substituted and a 4- to12-membered saturated heterocyclic group which is substituted orunsubstituted, wherein each R is independently selected from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl and a 5- to 12-membered aryl or heteroarylgroup, the group being unsubstituted or substituted, or when two groupsR are attached to an N atom they form, together with the N atom, a 4- to7-membered saturated N-containing heterocyclic ring; p is 1 or 2 and qis 0, 1 or 2.

R⁵ is selected from C₁-C₆ alkoxy, OR⁶, SR⁶, S(O)_(p)R⁶, nitro, CN,halogen, —C(O)R⁶, —CO₂R⁶, —C(O)N(R⁶)₂ and —N(R⁶)₂. R⁶, each of which isthe same or different when more than one is present in a givensubstituent, is selected from H, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl, andp is 1 or 2.

A halogen or halo group is F, Cl, Br or I. Preferably it is F, Cl or Br.A C₁-C₆ alkyl group substituted by halogen may be denoted by the term“halo-C₁-C₆ alkyl”, which means an alkyl group in which one or morehydrogens is replaced by halo. A halo-C₁-C₆ alkyl group preferablycontains one, two or three halo groups. A preferred example of such agroup is trifluoromethyl.

A C₁-C₆ alkoxy group is linear or branched. It is typically a C₁-C₄alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy,n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C₁-C₆ alkoxygroup is unsubstituted or substituted, typically by one or more groups Zor R⁵ as defined above.

A C₃-C₁₀ cycloalkyl group may be, for instance, C₃-C₈ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.Typically it is C₃-C₆ cycloalkyl. A C₃-C₁₀ cycloalkyl group isunsubstituted or substituted, typically by one or more groups Z or R⁵ asdefined above.

A 4- to 7-membered saturated N-containing heterocyclic ring typicallycontains one nitrogen atom and either an additional N atom or an O or Satom, or no additional heteroatoms. It may be, for example, azetidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine orhomopiperazine.

A 4- to 7-membered saturated N-containing heterocyclic ring as definedabove is unsubstituted or substituted on one or more ring carbon atomsand/or on any additional N atom present in the ring. Examples ofsuitable substituents include one or more groups Z or R⁵ as definedabove, and a C₁-C₆ alkyl group which is unsubstituted or substituted bya group Z or R⁵ as defined above.

Specific examples of a 4- to 7-membered saturated N-containingheterocyclic ring which is substituted as defined above include thefollowing structures:

A 5- to 7-membered saturated O-containing heterocyclic ring contains atleast one O atom and 0, 1 or 2, typically 0 or 1, additional heteroatomsselected from O, N and S. It is, for instance, tetrahydrofuran,tetrahydropyran, oxetane or morpholine.

A 3- to 12-membered saturated carbocyclic group is a 3-, 4-, 5-, 6-, 7-,8-, 9-, 10, 11- or 12-membered carbocyclic ring containing onlysaturated bonds. It is a monocyclic or fused bicyclic ring system. Itis, for instance, a 3- to 7-membered saturated carbocyclic ring.Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexaneand cycloheptane, and bicyclic ring systems in which two such rings arefused together. Specific examples of a 3- to 12-membered saturatedcarbocyclic group include the following structures:

A 5- to 12-membered unsaturated carbocyclic group is a 5-, 6-, 7-, 8-,9-, 10, 11- or 12-membered carbocyclic ring containing at least oneunsaturated bond. It is a monocyclic or fused bicyclic ring system. Thegroup is non-aromatic or aromatic, for instance aryl. Thus, in oneembodiment, a 5- to 12-membered unsaturated carbocyclic group is a 5- to12-membered aryl group. Examples of a 5- to 12-membered unsaturatedcarbocyclic group include benzene, naphthalene, indane, indene andtetrahydronaphthalene rings, or phenyl, naphthyl, indanyl, indenyl andtetrahydronaphthyl groups. The group is unsubstituted or substituted,typically by one or more groups Z or R⁵ as defined above. Specificexamples of a 5- to 12-membered unsaturated carbocyclic group includethe following structure:

An aryl group is a 5- to 12-membered aromatic carbocyclic group. It ismonocyclic or bicyclic. Examples include phenyl and naphthyl groups. Thegroup is unsubstituted or substituted, for instance by a group Z or R⁵as defined above. Specific examples of an aryl group include thefollowing structures:

A 5- to 12-membered unsaturated heterocyclic group is a 5-, 6-, 7-, 8-,9-, 10, 11- or 12-membered heterocyclic ring containing at least oneunsaturated bond and at least one heteroatom selected from O, N and S.It is a monocyclic or fused bicyclic ring system. The group isnon-aromatic or aromatic, for instance heteroaryl. Thus, in oneembodiment a 5- to 12-membered unsaturated heterocyclic group is a 5- to12-membered heteroaryl group. The 5- to 12-membered unsaturatedheterocyclic group may be, for example, furan, thiophene, pyrrole,pyrrolopyrazine, pyrrolopyrimidine, pyrrolopyridine, pyrrolopyridazine,indole, isoindole, pyrazole, pyrazolopyrazine, pyrazolopyrimidine,pyrazolopyridine, pyrazolopyridazine, imidazole, imidazopyrazine,imidazopyrimidine, imidazopyridine, imidazopyridazine, benzimidazole,benzodioxole, benzodioxine, benzoxazole, benzothiophene, benzothiazole,benzofuran, indolizinyl, isoxazole, oxazole, oxadiazole, thiazole,isothiazole, thiadiazole, dihydroimidazole, dihydrobenzofuran,dihydrodioxinopyridine, dihydropyrrolopyridine, dihydrofuranopyridine,dioxolopyridine, pyridine, quinoline, isoquinoline, purine, quinoxaline,tetrahydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline,5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine,5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine, thienopyrazine, pyrimidine,pyridazine, pyrazine, triazine, triazole or tetrazole. The group isunsubstituted or substituted, typically by one or more groups Z or R⁵ asdefined above. Specific examples of a 5- to 12-membered unsaturatedheterocyclic group include the following structures:

Heteroaryl is a 5- to 12-membered aromatic heterocyclic group whichcontains 1, 2, 3, or 4 heteroatoms selected from O, N and S. It ismonocyclic or bicyclic. Typically it contains one N atom and 0, 1, 2 or3 additional heteroatoms selected from O, S and N. It may be, forexample, a 5- to 7-membered heteroaryl group. Typically it is selectedfrom the heteroaryl groups included in the above list of options for a 5to 12-membered unsaturated heterocyclic group.

A 4- to 12-membered saturated heterocyclic group is a 4-, 5-, 6-, 7-,8-, 9-, 10, 11- or 12-membered heterocyclic ring which contains 1, 2, 3,or 4 heteroatoms selected from O, N and S. It is a monocyclic or fusedbicyclic ring system. Examples of such heterocyclic rings include, butare not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, dithianyl, dithiolanyl, imidazolidinyl,3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, andazabicyclo[2.2.2]hexanyl. Spiro moieties are also included within thescope of this definition. In one embodiment the saturated 4- to12-membered saturated heterocyclic group is a 4- to 7-membered saturatedN-containing heterocyclic ring as defined above, which is unsubstitutedor substituted. The saturated 4- to 12-membered heterocyclic group isunsubstituted or substituted, typically by one or more groups Z or R⁵ asdefined above. Further specific examples of a 4- to 12-memberedsaturated heterocyclic group (in which the heteroatom is O) include thefollowing structures:

Examples of a 4- to 7-membered saturated N-containing heterocyclic ringwhich is fused to a second ring as defined above to form aheteropolycyclic ring system include a group selected from azetidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine andhomopiperazine, said group being fused to a second ring as definedabove. The second ring is typically a 4- to 7-membered saturatedN-containing heterocyclic ring as defined above or a 5- to 12-memberedunsaturated heterocyclic group. More typically the second ring is a 5-,6- or 7-membered saturated N-containing heterocyclic ring or a 5- to7-membered unsaturated heterocyclic ring. Typical examples of the secondring include azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, homopiperazine, pyrrole, imidazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran and tetrahydropyran.Examples of the resulting heteropolycyclic system includeoctahydro-pyrrolo[1,2-a]pyrazine and octahydro-pyrrolo[3,4-c]pyrrole.Specific examples of the heteropolycyclic system include the followingstructures:

Examples of a 4- to 7-membered saturated N-containing heterocyclic groupas defined above which includes a bridgehead group (CR′₂)_(n)— or(CR′₂)_(r)—O—(CR′₂)_(s)— as defined above include3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane,8-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[2.2.1]heptane,3,6-diaza-bicyclo[3.1.1]heptane, 6-aza-bicyclo[3.1.1]heptane,3,9-diaza-bicyclo[4.2.1]nonane and 3-oxa-7,9-diazabicyclo[3.3.1]nonane.

Specific examples of this group include the following structures:

Examples of a group of formula (IIb) as defined above include groupsderived from a 4- to 7-membered saturated N-containing heterocyclicgroup as defined above which is spiro-fused at any available ring carbonatom to a 3 to 12-membered saturated carbocyclic ring, typically to a 3-to 6-membered saturated carbocyclic ring, or to a 4- to 7-memberedsaturated N-containing heterocyclic group. Examples include a groupselected from azetidine, pyrrolidine, piperidine and piperazine which isspiro-fused at a ring carbon atom to a group selected from cyclopropane,cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine,piperidine, piperazine and tetrahydropyran.

The group of formula (IIb) may, for instance, be a group derived from3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane or 2,7-diazaspiro[4.4]nonane. Specificexamples of a group of formula (IIb) include the following structures:

R⁴ is an indolyl group which is unsubstituted or substituted. Theindolyl group may be linked to the thiazolopyrimidine core via anyavailable ring position. It may, for instance, be an indol-4-yl,indol-5-yl, indol-6-yl or indol-7-yl group. Typically it is indol-4-ylor indol-6-yl, more typically an indol-4-yl group.

When substituted, the indolyl may be substituted at one or moreavailable ring positions. Typically it bears a substituent on thebenzene moiety of the indole group. For instance, an indol-4-yl group istypically substituted at the 5-, 6- or 7-position, more typically at the5- or 6-position. An indol-5-yl group is typically substituted at the4-, 6- or 7-position, more typically at the 4- or 6-position. Anindol-6-yl group is typically substituted at the 4-, 5- or 7-position,more typically at the 4- or 5-position. An indol-7-yl group is typicallysubstituted at the 4-, 5- or 6-position, more typically at the 5- or6-position.

When the indolyl group is substituted it may be substituted by a group Zor R⁵ as defined above. In a typical embodiment the indolyl group issubstituted by a group selected from R, —OR, —SR, —S(O)_(p)R, CH₂OR,—C(O)R, —CO₂R, CF₃, CF₂OH, CH(CF₃)OH, C(CF₃)₂OH, —(CH₂)_(q)OR,—(CH₂)_(q)NR₂, —C(O)N(R)₂, —NR₂, —N(R)C(O)R, —S(O)_(p)N(R)₂, —OC(O)R,OC(O)N(R)₂, —N(R)S(O)_(p)R, —NRC(O)N(R)₂, CN, halo, —NO₂ and a5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selectedfrom O, N and S, wherein R, p and q are as defined above in thedefinition of Z. In another typical embodiment the indolyl group issubstituted by a group selected from C₁-C₆ alkyl, CN, halo, —C(O)NR₂,halo(C₁-C₆)alkyl such as CF₃, NO₂, OR, SR, NR₂, C(O)R, SOR, SO₂R,SO₂NR₂, NRC(O)R, CO₂R and a 5-membered heteroaryl group as definedabove. In another more typical embodiment the indolyl group issubstituted by a group selected from CN, halo, —C(O)NR₂,halo(C₁-C₆)alkyl such as CF₃, —SO₂R, —SO₂NR₂, and a 5-memberedheteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, Nand S. In the above embodiments R is typically H or C₁-C₆ alkyl.

Typically the substituent on the indolyl group is anelectron-withdrawing group. When the substituent is a 5-memberedheteroaryl group it may be, for example, furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole,oxadiazole, thiazole, isothiazole, or thiadiazole.

In one embodiment a substituted indolyl group is an indol-4-yl groupsubstituted at the 5- or 6-position, in particular the 6-position, byCN, halo, —C(O)NH₂, —CF₃, —SO₂Me, —SO₂NMe₂ or a 5-membered heteroarylgroup as defined above. Typically the indol-4-yl group is substituted atthe 5- or 6-position by halo, in particular by F. More typically theindol-4-yl group is substituted at the 6-position by halo, in particularby F.

The parameter m in formula (I) is 0, 1 or 2. Typically m is 1 or 2. Moretypically m is 1.

In formulae (I), a 4- to 12-membered saturated heterocyclic group in thedefinitions of R¹ and R² may be a 4- to 7-membered saturatedN-containing heterocyclic ring which includes 0 or 1 additionalheteroatoms selected from N, S and O. A 5- to 12-membered unsaturatedheterocyclic group in the definitions of R′ and R² may be a 5- to12-membered heteroaryl group. A 5- to 12-membered unsaturatedcarbocyclic group in the definitions of R¹ and R² may be a 5- to12-membered aryl group.

In one aspect the invention provides a compound which is athiazolopyrimidine of formula (I):

wherein

W represents a thiazole ring;

R¹ and R² form, together with the N atom to which they are attached, agroup of the following formula (IIa):

-   -   in which A is selected from:    -   (a) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O, the ring being unsubstituted or substituted;    -   (b) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O, the ring being fused to a second ring selected from a 4-        to 7-membered saturated N-containing heterocyclic ring as        defined above, a 5- to 12-membered unsaturated heterocyclic        ring, a 5- to 7-membered saturated O-containing heterocyclic        ring, a 3- to 12-membered saturated carbocyclic ring and an        unsaturated 5- to 12-membered carbocyclic ring to form a        heteropolycyclic ring system, the heteropolycyclic ring system        being unsubstituted or substituted;    -   (c) a 4- to 7-membered saturated N-containing heterocyclic ring        which includes 0 or 1 additional heteroatoms selected from N, S        and O and which further comprises, linking two constituent atoms        of the ring, a bridgehead group selected from —(CR′₂)_(n)— and        (CR′₂)_(r)—O—(CR′₂)_(s)— wherein each R′ is independently H or        C₁-C₆ alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the        remaining ring positions being unsubstituted or substituted; and    -   (d) a group of formula (IIb):

-   -    wherein ring B is a 4- to 7-membered saturated N-containing        heterocyclic ring which includes 0 or 1 additional heteroatoms        selected from N, S and O and ring B′ is a 3- to 12-membered        saturated carbocyclic ring, a 5- to 7-membered saturated        O-containing heterocyclic ring or a 4- to 7-membered saturated        N-containing heterocyclic ring as defined above, each of B and        B′ being unsubstituted or substituted;    -   or one of R¹ and R² is C₁-C₆ alkyl and the other is a 4- to        7-membered saturated N-containing heterocyclic ring as defined        above or a C₁-C₆ alkyl group which is substituted by a 4- to        7-membered saturated N-containing heterocyclic ring group as        defined above;    -   m is 0, 1 or 2;    -   R³ is H or C₁-C₆ alkyl; and    -   R⁴ is an indole group which is unsubstituted or substituted;    -   or a pharmaceutically acceptable salt thereof.

The thiazole ring W in formula (I) adopts either of the two availableregiochemical orientations. Thus, in one embodiment thethiazolopyrimidine is of the following formula (Ia):

wherein R¹, R², R³, R⁴ and m are as defined above for formula (I).

In a second embodiment the thiazolopyrimidine is of the followingformula (Ib):

wherein R¹, R², R³, R⁴ and m are as defined above for formula (I).

Specific examples of compounds of the invention include the compoundlisted in the following Table:

TABLE 1 Compound No. Structure Name 1

5-(6-Fluoro-1H-indol-4-yl)-2- (hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[4,5- d]pyrimidine 2

5-(6-Fluoro-1H-indol-4-yl)-2- (hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4- d]pyrimidine 3

2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl- thiazolo[5,4-d]pyrimidine 4

2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin- 4-yl-thiazolo[5,4-d]pyrimidine 5

2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin- 4-yl-thiazolo[5,4-d]pyrimidine 6

2-(3,8-Diaza-bicyclo[3.2.1]oct-3- ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine 7

2-(4-Azetidin-1-yl-piperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl- thiazolo[5,4-d]pyrimidine 8

2-[(S)-1-(Hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)methyl]-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4- d]pyrimidine 9

2-(3,5-Dimethyl-piperazin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl- thiazolo[5,4-d]pyrimidine 10

2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin- 4-yl-thiazolo[4,5-d]pyrimidineformate 11

5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-yl-piperidin-1-ylmethyl)- thiazolo[4,5-d]pyrimidine 12

2-(3,3-Dimethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4- ylthiazolo[4,5-d]pyrimidine 13

5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1- ylmethyl)thiazolo[4,5-d]pyrimidine14

5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4- morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine 15

5-(5-Fluoro-1H-indol-4-yl)-2-[(S)-1- (hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-7-morpholin-4-ylthiazolo[4,5- d]pyrimidine 16

2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)- 5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine 17

2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4- ylthiazolo[4,5-d]pyrimidine 18

2-(4-Cyclopropylmethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine 19

{1-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine 20

{1-[5-(1H-Indol-4-yl)-7-morpholin-4- ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine 21

2-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin- 2-ylmethyl]-piperazin-1-yl}-isobutyramide 22

2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin- 4-ylthiazolo[5,4-d]pyrimidine 23

5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-piperazin-1-ylmethylthiazolo[5,4- d]pyrimidine 24

2-(4-Cyclopropylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin- 4-ylthiazolo[5,4-d]pyrimidine 25

2-{4-[5-(1H-Indol-4-yl)-7-morpholin-4- ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide 26

2-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide 27

{1-[5-(1H-Indol-4-yl)-7-morpholin-4- ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine 28

5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4- morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine 29

5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1- ylmethyl)thiazolo[5,4-d]pyrimidineand the pharmaceutically acceptable salts thereof.

A suitable synthetic strategy for producing a thiazolopyrimidine offormula (I) employs the precursor carboxaldehyde of formula (III):

wherein W is as defined above. Starting from this precursor thesynthesis comprises performing, in either order, a reductive aminationand a palladium-mediated (Suzuki-type) cross-coupling reaction.

A compound of the invention may thus be produced by a process whichcomprises treating a compound of formula (III):

wherein W is as defined above, with an amine of formula NHR^(1a)R^(2a)in which R^(1a) and R^(2a) are as defined above for R¹ and R² or R^(1a)and R^(2a) are as defined above for R¹ and R² wherein an N atom ispresent and is protected by an amine protecting group, in the presenceof a suitable reducing agent; treating the resulting compound of formula(IV):

wherein W, R^(1a) and R^(2a) are as defined above, with a boronic acidor ester thereof of formula R⁴B(OR¹⁵)₂ in which R⁴ is as defined aboveand each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form, togetherwith the boron atom to which they are attached, a pinacolato boronateester group, in the presence of a Pd catalyst; and, if R^(1a) and/orR^(2a) includes an amine protecting group, removing the protectinggroup. Any suitable amine protecting groups may be used in R^(1a) and/orR^(2a), for instance a butoxycarbonyl (BOC) group.

A compound of formula (I) may also be produced by a process whichcomprises treating a compound of formula (III):

wherein W is as defined above, with a boronic acid or ester thereof offormula R⁴B(OR¹⁵)₂ in which R⁴ is as defined above and each R¹⁵ is H orC₁-C₆ alkyl, or the two groups OR¹⁵ form, together with the boron atomto which they are attached, a pinacolato boronate ester group, in thepresence of a Pd catalyst; treating the resulting compound of formula(V):

wherein W and R⁴ are as defined above, with an amine of formulaNHR^(1a)R^(2a) in which R^(1a) and R^(2a) are as defined above, in thepresence of a suitable reducing agent; and, if R^(1a) and/or R^(2a)includes an amine protecting group, removing the protecting group. Inthis embodiment of the process the N atom of the indole group R⁴ may, ifnecessary, be protected before the compound of formula (V) is treatedwith the amine of formula NHR^(1a)R^(2a) for instance as discussedfurther below and as shown in scheme 5 which follows. In that case theindole protecting group is removed in a subsequent step.

Both the reductive amination step and the Pd-mediated cross-couplingstep take place under conventional conditions. The palladium catalystmay be any that is typically used for Suzuki-type cross-couplings, suchas PdCl₂(PPh₃)₂. The reducing agent in the amination step is typically aborohydride, for instance NaBH(OAc)₃, NaBH₄ or NaCNBH₃, in particularNaBH(OAc)₃.

A compound of formula (III) as defined above may be produced by aprocess which comprises oxidizing a compound of formula (VI):

wherein W is as defined above under suitable conditions. The oxidationmay be performed, for instance, using SeO₂ in dioxane.

A compound of formula (III) as defined above may also be produced by aprocess which comprises treating a compound of formula (VII):

wherein W is as defined above, with a deprotonating agent and then withdimethylformamide at −78° C. rising to room temperature. A suitabledeprotonating agent is a lithiating agent, for instance an alkyllithiumsuch as n-butyllithium in the presence of trimethylethylenediamine inTHF at −78° C.

A compound of formula (VI) or (VII) as defined above may be produced bya process which comprises treating a compound of formula (VIII):

wherein W is as defined above and R″ is H or CH₃ with a chlorinatingagent followed by morpholine in a suitable solvent, for instancemethanol at room temperature. A suitable chlorinating agent is POCl₃ inPhNMe₂. This reaction is suitably conducted at about 100° C.

A compound of formula (VIII) may be prepared by known methodologies orby analogy with known methodologies. For instance, included withinformula (VIII) are compounds of the following formulae (VIIIa) and(VIIIb):

These may be prepared, respectively, as shown in schemes 1 and 2 whichfollow, where they feature as synthetic intermediates.

A further compound of formula (VIII) has the following formula (VIIIc):

This compound may be prepared as described in the literature, forinstance in M. Sekiya, Y. Osaki Chem. Pharm. Bull., 1965, 13, 1319±1325;S. J. Childress, R. L. McKee, J. Am. Chem. Soc., 1952, 73, 3862±3864;and U.S. Pat. No. 2,933,498.

An alternative synthetic strategy for producing a thiazolopyrimidine offormula (I) entails attaching the group R⁴ to the thiazolopyrimidinecore by Suzuki coupling and then protecting the indole N atom of thegroup R⁴, prior to introduction of the —CHO moiety which is submitted toreductive amination. The process comprises oxidising a compound offormula (IX):

in which W is as defined above and R^(4a) is a group R⁴ as defined abovein which the indole N atom is protected, under suitable conditions. Theindole N atom is protected by any suitable protecting group, forinstance a toluenesulphonyl group. The oxidation may be performed, forinstance, using SeO₂ in dioxane. This reaction yields a compound of thefollowing formula (X):

in which W and R^(4a) are as defined above. The compound of formula (X)is then subjected to reductive amination by treatment with a compoundNHR^(1a)R^(2a) defined above. Any protecting groups are removedsubsequently. This strategy is illustrated in scheme 5 which follows.

Thiazolopyrimidines of formula (I) may be converted intopharmaceutically acceptable salts, and salts may be converted into thefree compound, by conventional methods. Pharmaceutically acceptablesalts include salts of inorganic acids such as hydrochloric acid,hydrobromic acid and sulfuric acid, and salts of organic acids such asacetic acid, oxalic acid, malic acid, methanesulfonic acid,trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. Inthe case of compounds of the invention bearing a free carboxysubstituent, the salts include both the above-mentioned acid additionsalts and the salts of sodium, potassium, calcium and ammonium. Thelatter are prepared by treating the free thiazolopyrimidine of formula(I), or an acid addition salt thereof, with the corresponding metal baseor ammonia.

Compounds of the present invention have been found in biological teststo be inhibitors of PI3 kinase. The compounds are selective for thep110δ isoform, which is a class Ia PI3 kinase, over other class Ia PI3kinases. They are thus selective for the p110δ isoform over both thep110α isoform and the p110β isoform. In particular they are selectivefor p110δ over p110β. The compounds are also selective for the p110δisoform over p110γ, which is a class Ib kinase.

The selectivity exhibited by compounds of the invention for p110δ overother isoforms of PI3 kinase is at least 2-fold. Typically theselectivity is 5-fold, or 10-fold, or 20-fold, or 50-fold, rising to100-fold or higher in many cases. Thus the compounds may be 2-fold,5-fold, 10-fold, 20-fold, 50-fold or 100-fold selective for p110δ overp110β. They may also be 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or100-fold selective for p110δ over p110α or over p110γ.

A compound of the present invention may be used as an inhibitor of PI3kinase, in particular of a class Ia PI3 kinase. Accordingly, a compoundof the present invention can be used to treat a disease or disorderarising from abnormal cell growth, function or behaviour associated withPI3 kinase, in particular the p1106 isoform of PI3 kinase. Examples ofsuch diseases and disorders are discussed by Drees et al in Expert Opin.Ther. Patents (2004) 14(5):703-732. These include proliferativedisorders such as cancer, immune disorders, cardiovascular disease,viral infection, inflammation, metabolism/endocrine disorders andneurological disorders. Examples of metabolism/endocrine disordersinclude diabetes and obesity. Examples of cancers which the presentcompounds can be used to treat include leukaemia, brain tumours, renalcancer, gastric cancer and cancer of the skin, bladder, breast, uterus,lung, colon, prostate, ovary and pancreas.

A compound of the present invention may be used as an inhibitor of PI3kinase. A human or animal patient suffering from a disease or disorderarising from abnormal cell growth, function or behaviour associated withP13 kinase, in particular with the p110δ isoform of PI3 kinase such asan immune disorder, cardiovascular disease, viral infection,inflammation, a metabolism/endocrine disorder or a neurologicaldisorder, may thus be treated by a method comprising the administrationthereto of a compound of the present invention as defined above. A humanor animal patient suffering from cancer may also be treated by a methodcomprising the administration thereto of a compound of the presentinvention as defined above. The condition of the patient may thereby beimproved or ameliorated.

A compound of the present invention can be administered in a variety ofdosage forms, for example orally such as in the form of tablets,capsules, sugar- or film-coated tablets, liquid solutions or suspensionsor parenterally, for example intramuscularly, intravenously orsubcutaneously. The compound may therefore be given by injection orinfusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Daily dosagescan vary within wide limits and will be adjusted to the individualrequirements in each particular case. Typically, however, the dosageadopted for each route of administration when a compound is administeredalone to adult humans is 0.0001 to 50 mg/kg, most commonly in the rangeof 0.001 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such adosage may be given, for example, from 1 to 5 times daily. Forintravenous injection a suitable daily dose is from 0.0001 to 1 mg/kgbody weight, preferably from 0.0001 to 0.1 mg/kg body weight. A dailydosage can be administered as a single dosage or according to a divideddose schedule.

A compound of the invention is formulated for use as a pharmaceutical orveterinary composition also comprising a pharmaceutically orveterinarily acceptable carrier or diluent. The compositions aretypically prepared following conventional methods and are administeredin a pharmaceutically or veterinarily suitable form. The compound may beadministered in any conventional form, for instance as follows:

A) Orally, for example, as tablets, coated tablets, dragees, troches,lozenges, aqueous or oily suspensions, liquid solutions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose,dextrose, saccharose, cellulose, corn starch, potato starch, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, maize starch, alginic acid, alginates or sodium starchglycolate; binding agents, for example starch, gelatin or acacia;lubricating agents, for example silica, magnesium or calcium stearate,stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners,wetting agents such as lecithin, polysorbates or lauryl sulphate. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. Such preparations may be manufactured in a knownmanner, for example by means of mixing, granulating, tableting, sugarcoating or film coating processes.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is present as such, ormixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia;dispersing or wetting agents may be naturally-occurring phosphatides,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides for example polyoxyethylene sorbitan monooleate.

The said aqueous suspensions may also contain one or more preservatives,for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by this addition of an antioxidant such as ascorbicacid. Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids an hexitol anhydrides,for example sorbitan mono-oleate, and condensation products of the saidpartial esters with ethylene oxide, for example polyoxyethylene sorbitanmonooleate. The emulsion may also contain sweetening and flavouringagents. Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, sorbitol or sucrose. In particular a syrup fordiabetic patients can contain as carriers only products, for examplesorbitol, which do not metabolise to glucose or which only metabolise avery small amount to glucose.

Such formulations may also contain a demulcent, a preservative andflavouring and coloring agents.

B) Parenterally, either subcutaneously, or intravenously, orintramuscularly, or intrasternally, or by infusion techniques, in theform of sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using thosesuitable dispersing of wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicpaternally-acceptable diluent or solvent, for example as a solution in1,3-butane diol.

Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition fattyacids such as oleic acid find use in the preparation of injectables.

C) By inhalation, in the form of aerosols or solutions for nebulizers.

D) Rectally, in the form of suppositories prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperature but liquid at the rectal temperature and will therefore meltin the rectum to release the drug. Such materials are cocoa butter andpoly-ethylene glycols.

E) Topically, in the form of creams, ointments, jellies, collyriums,solutions or suspensions.

The invention will be further described in the Examples which follow:

EXAMPLES General Synthetic Procedure

The following general schemes 1 to 6 illustrate routes to compounds offormula (I). Schemes 7 and 8 illustrate routes to intermediates used inthe synthesis of compounds of formula (I).

General Experimental Details: NMR Spectroscopy

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer witha 5 mm inverse detection triple resonance probe operating at 400 MHz oron a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detectiontriple resonance TXI probe operating at 400 MHz or on a Bruker AvanceDPX 300 spectrometer with a standard 5 mm dual frequency probe operatingat 300 MHz. Shifts are given in ppm relative to tetramethylsilane.

Purification by Column Chromatography

Compounds purified by column chromatography were purified using silicagel or Isolute® cartridge or Redisep® cartridge, eluting with gradientsfrom 100-0 to 0-100% of cyclohexane/EtOAc, or from 100-0 to 0-100%pentane/EtOAc or from 100-0 to 70-30% DCM/MeOH (with or without theaddition of NH₃ 0.1%). ‘Silica gel’ refers to silica gel forchromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silicagel 60), and an applied pressure of nitrogen up to 10 p.s.i acceleratedcolumn elution. Where thin layer chromatography (TLC) has been used, itrefers to silica gel TLC using plates, typically 3×6 cm silica gel onaluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka60778).

Purification by Preparative HPLC:

Compounds purified by preparative HPLC were purified using aC18-reverse-phase column (100×22.5 mm i.d Genesis column with 7 μmparticle size, UV detection at 230 or 254 nm, flow 5-15 mL/min), or aPhenyl-Hexyl column (250×21.2 mm i.d. Gemini column with 5 μm particlesize, UV detection at 230 or 254 nm, flow 5-20 ml/min), eluting withgradients from 100-0% to 0-100% water/acetonitrile or water/MeOHcontaining 0.1% TFA or water/acetonitrile containing 0.1% formic acid.The free base was liberated by partitioning between EtOAc and a sat.solution of sodium bicarbonate. The organic layer was dried (MgSO₄) andconcentrated in vacuo. Alternatively, the free base was liberated bypassing through an Isolute® SCX-2 cartridge, eluting with NH₃ inmethanol.

Microwave Reactions:

Microwave experiments were carried out using either a Personal ChemistrySmith Synthesiser or a Biotage Initiator™, which uses a single-moderesonator and dynamic field tuning, both of which give reproducibilityand control. Temperatures from 40-250° C. can be achieved and pressuresof up to 20 bar can be reached.

All solvents and commercial reagents were used as received.Non-commercially available reagents/reactants were prepared according toprocedures described in the literature.Abbreviations used in the experimental section:aq.=aqueousBOC=t-Butoxycarbonylbs=broad singlet (NMR)Cs₂CO₃=cesium carbonated=doublet (NMR)DCM=dichloromethaneDIPEA=diisopropylethylamineDMA=dimethylacetamideDMAP=dimethylaminopyridineDMF=dimethylformamideDMSO=dimethylsulfoxideeq.=equivalentsEtOAc=ethyl acetateEtOH=ethanolh=hour(s)HATU=O-(7-Azabenzotriazol-1-yl)—N,N,N′,N′-tetramethyluroniumhexafluorophosphateHCl=hydrochloric acidH₂O=waterHPLC=high pressure liquid chromatographyIMS=industrial methylated spiritiPrOH=isopropanolLCMS=liquid chromatography mass spectrometryM=molarm=multiplet (NMR)MeOH=methanolmg=milligramMgSO₄=magnesium sulphatemin=minute(s)mL=millilitreNa₂CO₃=sodium carbonateNaHCO₃=sodium hydrogen carbonateNaOH=sodium hydroxideNa₂SO₄=sodium sulfateNMR=nuclear magnetic resonanceq=quartet (NMR)Rt=retention timeRT=room temperaturesat=saturatedt=triplet (NMR)TBAF=tetrabutylammonium fluorideTBS=t-butyldimethylsilylTFA=trifluoroacetic acidTHF=tetrahydrofuranTLC=thin layer chromatographyXant phos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Reference Example 1 Formation of Boronate Ester

The boronate ester product of the final step of schemes 1 to 4 above wasprepared as follows. To a solution of halide (1 eq.) andbis(pinacolato)diboron (1.3 eq.) in DMSO were added KOAc (3 eq.) and[1,1′-bis(diphenylphosphine)ferrocene]-dichloropalladium (0.05 eq.). Themixture was heated at 90° C. until completion of the reaction. Thereaction mixture was pardoned between EtOAc and H₂O. The organic layerwas washed successively with H₂O and brine, dried over Na₂SO₄ andevaporated to dryness. The resultant residue was then purified by columnchromatography.

Reference Example 2 Suzuki Coupling

The following methods were used for the Suzuki coupling reactionsdepicted in schemes A and B above:

Method A

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Na₂CO₃(2 eq.), the appropriate indole boronate ester (1.5 eq.) andbis(triphenylphosphine)palladium (II) chloride (0.1 eq.) inacetonitrile/water (2:1) was heated at 140° C. for 20-50 min in amicrowave reactor. The resulting mixture was diluted with water thenextracted with ethyl acetate. The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo then purified by eitherpreparative HPLC or column chromatography to give the desired product.Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. Theresulting residue was then purified by either preparative HPLC or columnchromatography to give the desired product.

Method B

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs₂CO₃(1.5 eq.), the appropriate indole boronate ester or boronic acid (1.2eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) indioxane/water (3:1) was heated at 125° C., for 10-30 min in a microwavereactor. The resulting mixture was diluted with water then extractedwith ethyl acetate. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo then purified by either preparativeHPLC or column chromatography to give the desired product.Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. Theresulting residue was then purified by either preparative HPLC or columnchromatography to give the desired product.

Method C

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs₂CO₃(1.5 eq.), the appropriate indole boronic acid (1.2 eq.) andtetrakis(triphenylphosphine)palladium (0.05 eq.) in dioxane/water (3:1)was heated at 125° C., for 10-30 min in a microwave reactor. Theresulting mixture was diluted with water then extracted with ethylacetate. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo then purified by either preparative HPLC or columnchromatography to give the desired product. Alternatively, the reactionmixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOHthen eluted with 2 M NH₃ in MeOH. The resulting residue was thenpurified by either preparative HPLC or column chromatography to give thedesired product.

Method D

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs₂CO₃(1.5 eq.), the appropriate indole boronic acid (1.2 eq.) andtetrakis(triphenylphosphine)palladium (0.05 eq.) in acetonitrile/water(3:1) was heated at 125° C.-140° C., for 10-30 min in a microwavereactor. The resulting mixture was diluted with water then extractedwith ethyl acetate. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo then purified by either preparativeHPLC or column chromatography to give the desired product.Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. Theresulting residue was then purified by either preparative HPLC or columnchromatography to give the desired product.

Method E

A mixture of the appropriate 5-chloro-thiazolopyrimidine (1 eq.), Cs₂CO₃(1.5 eq.), the appropriate indole boronate ester (1.2 eq.) andtetrakis(triphenylphosphine)palladium (0.05 eq.) in acetonitrile/water(3:1) was heated at 140° C., for 10-30 min in a microwave reactor. Theresulting mixture was diluted with water then extracted with ethylacetate. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo then purified by either preparative HPLC or columnchromatography to give the desired product. Alternatively, the reactionmixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOHthen eluted with 2 M NH₃ in MeOH. The resulting residue was thenpurified by either preparative HPLC or column chromatography to give thedesired product.

Method F

A mixture of the appropriate 5-chloro-thiazolopyrimidine (1 eq.), Na₂CO₃(1.5 eq.), the appropriate indole boronate ester (1.2 eq.) andtetrakis(triphenylphosphine)palladium (0.1 eq.) in acetonitrile/water(2:1) was heated at 140° C., for 10-30 min in a microwave reactor. Theresulting mixture was diluted with water then extracted with ethylacetate. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo then purified by either preparative HPLC or columnchromatography to give the desired product. Alternatively, the reactionmixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOHthen eluted with 2 M NH₃ in MeOH. The resulting residue was thenpurified by either preparative HPLC or column chromatography to give thedesired product.

Method G

A mixture of the appropriate 5-chloro-thiazolopyrimidine (1 eq.), Na₂CO₃(1.5 eq.), the appropriate indole boronic acid (1.2 eq.) andtetrakis(triphenylphosphine)palladium (0.1 eq.) in acetonitrile/water(2:1) was heated at 140° C., for 10-30 min in a microwave reactor. Theresulting mixture was diluted with water then extracted with ethylacetate. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo then purified by either preparative HPLC or columnchromatography to give the desired product. Alternatively, the reactionmixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOHthen eluted with 2 M NH₃ in MeOH. The resulting residue was thenpurified by either preparative HPLC or column chromatography to give thedesired product

Reference Example 3 t-Butoxycarbonyl Deprotection

To a solution of the relevant BOC-protected thiazolopyrimidine in DCMwas added TFA and the resulting solution was stirred at RT for 30-180min. The resulting mixture was diluted with water, neutralised withsaturated aqueous solution of NaHCO₃ then extracted with DCM. Thecombined organic extracts were dried (MgSO₄ or Na₂SO₄), filtered andconcentrated in vacuo, then purified by either preparative HPLC orcolumn chromatography to give the desired product. Alternatively, thereaction mixture was loaded onto an Isolute® SCX-2 cartridge, washedwith MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue wasthen purified by either preparative HPLC or column chromatography togive the desired product.

Reference Example 4 TBS-Deprotection

To a solution of the relevant TBS-protected1H-indol-4-yl-thiazolopyrimidine in THF was added TBAF and the resultingsolution was stirred at RT for 30 min, then concentrated in vacuo.Alternatively, the resulting solution was diluted with brine thenextracted with DCM. The combined organic extracts were dried (MgSO₄ orNa₂SO₄), filtered and concentrated in vacuo. In either case, theresultant residue was purified by either preparative HPLC or columnchromatography to give the desired product.

Reference Example 5 5-Amino-2-methyl-thiazole-4-carboxylic acid ethylester

To a solution of acetylamino-cyano-acetic acid ethyl ester (27.2 g,0.160 mol) in anhydrous toluene (300 mL) was added Lawesson's reagent(32.0 g, 0.079 mol) and the resulting mixture heated at reflux for 18 h.The resulting yellow suspension was partitioned between an aqueoussolution of HCl (1 M) and tert-butyl methyl ether. The layers wereseparated and the organic layer extracted with an aqueous solution ofHCl (1 M). The combined aqueous layers was basified to pH 10 with anaqueous solution of NaOH (2 M), then extracted with EtOAc. The organiclayer was isolated, dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound as a pale yellow solid (17.0 g, 57%).

[M+H]⁺ 187.0

Reference Example 6 2-Methyl-5-ureido-thiazole-4-carboxylic acid ethylester

To a solution of 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester(15.0 g, 0.081 mol) in DCM (550 mL) was added chlorosulfonyl isocyanate(8.92 mL, 0.102 mol) dropwise at −78° C. The thick suspension wasallowed to warm to RT and stirred for 45 minutes. The resultingprecipitate was collected by filtration and dried in vacuo. Theresultant white solid was suspended in an aqueous solution of HCl (6 M,400 mL) and heated at 90° C. for 1 h. The resulting solution was cooledto 0° C. and pH adjusted to 5 with an aqueous solution of NaOH (6 M).The resultant precipitate was collected by filtration and dried in vacuoat 60° C. for 36 h to give the title compound (16.4 g, 89%).

[M+H]⁺ 230.0

Reference Example 7 2-Methyl-4H-thiazolo[5,4-d]pyrimidine-5,7-dione

To a suspension of 2-methyl-5-ureido-thiazole-4-carboxylic acid ethylester (21.0 g, 0.079 mol) in iPrOH (300 mL) was added an aqueoussolution of NaOH (3 M, 26 mL, 0.078 mol) at 80° C. The thick whitesuspension was heated at 80° C. for 45 min, then diluted with H₂O andcooled to 0° C. The reaction mixture was acidified to pH 3 and theprecipitate collected by filtration. The white solid was washed with H₂Oand dried in vacuo at 60° C. for 17 h to give the title compound as awhite solid (12.3 g, 83%).

¹H NMR (300 MHz, DMSO-d₆): δ 2.56 (s, 3H).

Reference Example 8 5,7-Dichloro-2-methyl-thiazolo[5,4-d]pyrimidine

To a mixture of 2-methyl-4H-thiazolo[5,4-d]pyrimidine-5,7-dione (7.5 g,0.041 mol) in N,N-dimethylaniline (3.7 mL, 0.029 mol) was addedphosphorous oxychloride (38.0 mL, 0.410 mol) and the mixture heated at130° C. for 4 h. The resulting black solution was cooled to RT, thencarefully quenched with crushed ice and H₂O, before being extracted withEtOAc. The organic layer was isolated, dried (MgSO₄) and concentrated invacuo to give a yellow solid. The solid was dissolved in DCM, thenwashed with an aqueous solution of NaHCO₃ followed by brine, dried(Na₂SO₄) and concentrated in vacuo to give the title compound as a paleyellow solid (4.90 g, 54%).

¹H NMR (300 MHz, CDCl₃): δ 2.95 (s, 3H).

Reference Example 95-Chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

To a solution of 5,7-dichloro-2-methyl-thiazolo[5,4-d]pyrimidine (4.1 g,18.72 mmol) in MeOH (100 mL) was added morpholine (3.26 mL, 37.44 mmol)at 0° C. and the mixture stirred at 0° C. for 30 minutes. The resultantprecipitate was collected by filtration and dried in vacuo at 40° C. togive the title compound as a cream solid (4.42 g, 89%).

¹H NMR (300 MHz, CDCl₃): δ 2.74 (s, 3H), 3.80-3.86 (m, 4H) and 4.35 (m,4H).

Reference Example 105-(1H-Indol-4-yl)-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared via the Suzuki coupling method of Reference Example 2, using5-Chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine. The titlecompound was obtained as a white solid (130 mg, 50%).

[M+H]⁺ 352.9

Reference Example 11 4-Hydroxy-2-methyl-thiazole-5-carboxylic acid ethylester

To a solution of thioacetamide (17.2 g, 0.229 mol) in toluene (130 mL)was added diethyl bromomalonate (55.0 g, 0.230 mol) and the mixtureheated at reflux for 3 h. The reaction mixture was cooled to RT,filtered through Celite, then concentrated in vacuo. The resultant solidwas triturated with hexane to give the title compound as a yellow solid(11.0 g, 26%).

¹H NMR (400 MHz, CDCl₃): δ 1.36 (t, J=7.1 Hz, 3H), 2.67 (s, 3H) and 4.35(q, J=7.1 Hz, 2H).

Reference Example 122-Methyl-4-(toluene-4-sulfonyloxy)-thiazole-5-carboxylic acid ethylester

To a solution of 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethylester (5.0 g, 26.74 mmol) in chloroform (80 mL) were addedp-toluenesulfonyl chloride (5.61 g, 29.41 mmol) and triethylamine (4.84mL, 34.76 mmol) at 0° C. The reaction mixture was allowed to warm to RTover 4 h, then diluted with DCM and H₂O. The organic layer was isolated,washed with H₂O and brine, then dried (MgSO₄) and concentrated in vacuo.The resultant residue was purified by column chromatography to give thetitle compound as a pale brown solid (8.1 g, 89%).

¹H NMR (400 MHz, CDCl₃): δ 1.34 (t, J=7.1 Hz, 3H), 2.47 (s, 3H), 2.64(s, 3H), 4.30 (q, J=7.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H) and 7.94 (d,J=8.1 Hz, 2H).

Reference Example 13 4-Benzylamino-2-methyl-thiazole-5-carboxylic acidethyl ester

To a solution of2-methyl-4-(toluene-4-sulfonyloxy)-thiazole-5-carboxylic acid ethylester (2.0 g, 5.865 mmol) in 1,4-dioxane (50 mL) was added benzylamine(1.92 mL, 17.6 mmol) and the mixture was heated at 120° C. for 6 h. Thereaction mixture was cooled to RT and partitioned between EtOAc and anaqueous solution of HCl (1 M). The organic layer was isolated, washedwith brine, then dried (MgSO₄) and concentrated in vacuo. The resultantresidue was purified by column chromatography to give the title compoundas a yellow solid (0.80 g, 49%).

¹H NMR (300 MHz, CDCl₃): δ 1.31 (t, J=7.1 Hz, 3H), 2.60 (s, 3H), 4.24(q, J=7.1 Hz, 2H), 4.76 (d, J=6.1 Hz, 2H), 7.07 (bs, 1H) and 7.21-7.38(m, 5H).

Reference Example 144-Benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione

To a solution of 4-benzylamino-2-methyl-thiazole-5-carboxylic acid ethylester (0.40 g, 1.45 mmol) in DCM (10 mL) was added chlorosulfonylisocyanate (140 μL, 1.59 mmol) dropwise at −78° C. The mixture wasallowed to warm to RT and stirred for 30 minutes. The resulting solutionwas concentrated in vacuo then dissolved in acetone (5 mL), before H₂O(2 mL) was added dropwise. The mixture was stirred at RT for 30 minutes,then concentrated in vacuo. The resultant oil was partitioned betweenEtOAc and H₂O. The organic layer was isolated, washed with brine, dried(MgSO₄) and concentrated in vacuo to give4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester as apale brown oil. To a solution of4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester inMeOH (10 mL) was added a solution of sodium methoxide in MeOH (25% w/w,1.33 mL, 5.80 mmol) and the mixture was stirred at RT for 18 h. Thecrude reaction mixture was concentrated in vacuo and partitioned betweenEtOAc and an aqueous solution of HCl (1 M). The organic layer wasisolated, washed with brine, then dried (MgSO₄) and concentrated invacuo. The resultant residue was triturated with EtOAc to give the titlecompound as a pale yellow solid (0.25 g, 63%).

¹H NMR (300 MHz, DMSO-d₆): δ 2.76 (s, 3H), 5.25 (s, 2H), 7.19-7.40 (m,5H) and 11.71 (s, 1H).

Reference Example 15 2-Methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione

Method A

To a solution of4-benzyl-2-methyl-4H-thiazolo[4,5-c]pyrimidine-5,7-dione (3.80 g, 13.87mmol) in xylene (40 mL) was added boron tribromide (5.34 mL, 55.47 mmol)dropwise at 120° C. The reaction mixture was heated at 170° C. for 1 h,then cooled to 0° C., before MeOH (30 mL) was carefully added. Theresultant precipitate was collected by filtration, washed with MeOHfollowed by H₂O, then dried in vacuo at 80° C. to give the titlecompound as a white solid (2.3 g, 91%).

¹H NMR (400 MHz, DMSO-d₆): δ 2.73 (s, 3H).

Method B

To a solution of6-benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione (6 g, 22 mmol)in xylene (120 mL) was added boron tribromide (8.3 mL, 88 mmol) dropwiseat 120° C. The reaction mixture was heated at 170° C. for 1 h, thencooled to 0° C., before MeOH (30 mL) was carefully added. The resultantprecipitate was collected by filtration, washed with MeOH followed byH₂O, then dried in vacuo at 50° C. to give the title compound as a whitesolid (4.0 g, 100%).

¹H NMR (400 MHz, DMSO): δ 2.73 (s, 3H).

Reference Example 16 5,7-Dichloro-2-methyl-thiazolo[4,5-d]pyrimidine

Prepared using the method used in the preparation of5,7-dichloro-2-methyl-thiazolo[5,4-d]pyrimidine using2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione in place of2-methyl-4H-thiazolo[5,4-d]pyrimidine-5,7-dione. The title compound wasobtained as an solid (140 mg, 28%).

¹H NMR (400 MHz, DMSO-d₆): δ 2.97 (s, 3H).

Reference Example 175-Chloro-2-methyl-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine

To a solution of 5,7-dichloro-2-methyl-thiazolo[4,5-d]pyrimidine (92 mg,0.42 mmol) in MeOH (3 mL) was added morpholine (81 μL, 0.93 mmol) andthe mixture stirred at RT for 1 h. The reaction mixture was diluted withEtOAc and H₂O. The organic layer was isolated, washed with brine, thendried (MgSO₄) and concentrated in vacuo. The resultant residue waspurified by column chromatography to give the title compound as a creamsolid (102 mg, 90%).

¹H NMR (400 MHz, CDCl₃): δ 2.85 (s, 3H), 3.80-3.86 (m, 4H) and 3.88-3.94(m, 4H).

Reference Example 185-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde

To a solution of5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine (102 mg,0.38 mmol) in 1,4-dioxane (5 mL) was added selenium dioxide (51 mg, 0.46mmol) and the solution heated at 105° C. for 6 h. The reaction mixturewas cooled to RT and partitioned between DCM and brine. The organiclayer was isolated, then dried (MgSO₄) and concentrated in vacuo. Theresultant residue was purified by column chromatography to give thetitle compound as an orange solid (53 mg, 49%).

¹H NMR (400 MHz, DMSO-d₆): δ 3.73-3.78 (m, 4H), 3.85-3.96 (m, 4H) and10.12 (s, 1H)

Reference Example 195-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic

To a solution of5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (25mg, 0.088 mmol) in 1,2-dichloroethane (1 mL) was addedhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (21mg, 0.10 mmol). The mixture was stirred at RT for 5 min before sodiumtriacetoxyborohydride (28 mg, 0.130 mmol) was added. The resultingsolution was stirred at RT for 1 h. The crude reaction mixture waspartitioned between DCM and brine. The organic layer was isolated, thendried (MgSO₄) and concentrated in vacuo. The resultant residue waspurified by column chromatography to give the title compound as a whitesolid (26 mg, 61%).

¹H NMR (400 MHz, CDCl₃): δ 1.55 (s, 9H), 2.70-2.83 (m, 4H), 2.88 (s,2H), 3.30 (s, 2H), 3.63 (s, 2H), 3.82-3.87 (m, 4H), 3.93-4.01 (m, 4H)and 4.05-4.17 (m, 2H).

Reference Example 20 1-(tert-Butyl-dimethyl-silanyl)-5-fluoro-1H-indole

To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF(250 mL) was added sodium hydride (60% suspension in mineral oil, 10.22g, 0.255 mol) portionwise and maintaining the solution at 0° C. Thereaction mixture was stirred at 0° C. for 20 min, then a solution oftert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF(20 mL) was added and the solution stirred at RT for 25 h. The reactionmixture was poured into H₂O and the layers separated. The aqueous layerwas extracted with EtOAc and the combined organic layers were dried(MgSO₄), then concentrated in vacuo. The resultant residue was purifiedby column chromatography (silica gel, cyclohexane:DCM 100% to 50:50) toprovide the title compound as a colourless oil (41.2 g, 74%).

¹H NMR (400 MHz, CDCl₃): δ 0.60 (s, 6H), 0.94 (s, 9H), 6.58 (dd, J=3.2,1.0 Hz, 1H), 6.87-6.93 (m, 1H), 7.23 (d, J=3.2 Hz, 1H), 7.24-7.29 (m,1H) and 7.41 (m, 1H).

Reference Example 21[1-(tert-Butyl-dimethyl-silanyl)-5-fluoro-1H-indol-4-yl]boronic acid

To a solution of 1-(tert-butyl-dimethyl-silanyl)-5-fluoro-1H-indole(30.0 g, 0.12 mol) in anhydrous THF (1000 mL) were addedN,N,N′,N′-tetramethylethylenediamine (36.6 mL, 0.241 mol) and a solutionof s-butyl lithium (1.4 M in cyclohexane, 172 mL, 0.241 mmol) at −78° C.The resulting mixture was stirred at −78° C. for 2 h, then triisopropylborate (37.5 mL, 162.7 mmol) was added dropwise. The resulting solutionwas stirred at −78° C. for 40 min, then allowed to warm to −20° C. Anaqueous solution of HCl (2.4 M, 250 mL) was added and the resultingmixture was poured into H₂O. The layers were separated and the aqueouslayer extracted with EtOAc. The combined organic layers were dried(MgSO₄) and concentrated in vacuo. The resultant yellow solid was thencrystallised from DCM and cyclohexane to give the title compound as awhite solid (25.0 g, 71%).

¹H NMR (400 MHz, CD₃OD): δ 0.62 (s, 6H), 0.92 (s, 9H), 6.51 (d, J=3.2Hz, 1H), 6.79-6.90 (m, 1H), 7.30-7.36 (m, 1H) and 7.54 (dd, J=9.0, 4.6Hz, 1H).

Reference Example 225-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Step 1

A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treatedat 0° C. with trifluoroacetic anhydride (6.1 mL, 42.6 mmol). After 30min, the reaction was poured into water and the resulting precipitatecollected by filtration, washed with water, then dried in vacuo. Thesolid was then dissolved in 10% aqueous NaOH (200 mL) and heated atreflux for 1 h. The reaction mixture was cooled to RT, washed with DCMand acidified with aqueous HCl. The resulting white precipitate wascollected by filtration, washed with water, taken up in DCM, washed withwater, dried (MgSO₄) and evaporated in vacuo. The resulting material (5g, 75%) was dissolved in methanol (80 mL) and treated with concentratedsulfuric acid (2 mL) then heated at reflux overnight. The reaction wascooled and the resulting precipitate collected, washed with water andconcentrated in vacuo to give 5-fluoro-1H-indole-3-carboxylic acidmethyl ester as a peach-coloured solid (4.5 g, 83%).

Step 2

A solution of thallium tris(trifluoroacetate) (8.45 g, 15.6 mmol) in TFA(35 mL) was added to a solution of 5-fluoro-1H-indole-3-carboxylic acidmethyl ester (2 g, 10.4 mmol) in TFA (10 mL) at room temperature andstirred for 2 h. The reaction mixture was evaporated in vacuo and theresulting residue suspended in water (25 mL) before being treated with asolution of potassium iodide (5.2 g, 31.3 mmol) in water (50 mL). Thereaction mixture was treated with dichloromethane (100 mL) and methanol(5 mL) and the resulting precipitate removed by filtration throughcelite. The organic layer was separated, washed successively with sodiumthiosulfate solution and brine, then dried (MgSO₄) and evaporated invacuo. The resultant material was dissolved in methanol (60 mL) andtreated with 40% aqueous NaOH solution (60 mL) then refluxed for 2 h.The reaction mixture was cooled to RT and extracted with DCM/MeOH (ratio95:5). The organic layer was dried (MgSO₄), filtered and concentrated invacuo. The resultant residue was purified by column chromatography(silica gel, pentane:EtOAc 75:25) to provide 5-fluoro-4-iodo-1H-indoleas a pale brown solid (1.05 g, 39%).

NMR δ_(H) (300 MHz, CDCl₃) 6.49-6.52 (m, 1H), 6.95 (apparent dt, J=0.4,8.6, 1H), 7.26-7.33 (m, 2H) and 8.35 (s, 1H).

Step 3

A solution of 5-fluoro-4-iodo-1H-indole (1.28, 4.90 mmol) in dioxane (5mL) was treated with triethylamine (1.0 mL, 7.18 mmol), palladiumacetate (22.0 mg, 0.098 mmol) and bis(cyclohexyl)phosphino-2-biphenyl(137 mg, 0.40 mmol) then heated to 80° C. A solution of pinacolborane (1M in THF, 13.0 mL, 13.0 mmol) was added via syringe. After 30 min, thereaction mixture was cooled to RT, then diluted with water (50 mL) andDCM (50 mL). The resulting mixture was passed through a phase separationcartridge, and the organic layer was concentrated in vacuo. Theresultant residue was purified by column chromatography (silica gel,pentane:EtOAc 75:25) to provide the title compound as a tan solid (1.06g, 83%).

[M+H]⁺ 262.1

Reference Example 23 1-Bromo-5-fluoro-2-methyl-3-nitro-benzene

To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) intrifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reactionmixture was stirred at RT for 16 h. The reaction mixture was then pouredonto ice and water and stirred for 15 min. The product was thenextracted into EtOAc and the organic layer washed with brine, dried(MgSO₄) and concentrated in vacuo to give the title compound as a paleoil which crystallised out on standing (11.76 g, 77%). NMR δ_(H) (300MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J=2.8, 7.6, 1H) and 7.58 (dd, J=2.9,7.4, 1H).

Reference Example 24 4-Bromo-6-fluoro-1H-indole

To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) andpyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100°C. for 3 h. The mixture was cooled to RT and concentrated in vacuo togive 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-1-methyl vinyl]-pyrrolidineas a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7mmol) and Raney®-Nickel (suspension in H₂O, 15 mL) in MeOH:THF (1:1, 150mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0° C. and themixture stirred at RT for 5 hours. The reaction mixture was thenfiltered through Celite and the filter cake washed with EtOAc. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by column chromatography (silica gel, pentane:EtOAc 75:25) toprovide the title compound as a pale oil (2.57 g, 37%).

NMR δ_(H) (300 MHz, CDCl₃) 6.57 (apparent t, J=2.7, 1H), 7.04 (dd,J=2.1, 9.1, 1H), 7.12 (dd, J=2.1, 9.1, 1H), 7.20-7.25 (m, 1H) and 8.25(s, 1H).

Reference Example 256-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

To a solution of 4-bromo-6-fluoro-1H-indole (6.0 g, 25.53 mmol) andbis(pinacolato)diboron (9.7 g, 38.19 mmol) in anhydrous DMSO (120 mL)were added KOAc (7.5 g, 76.41 mmol) and[1,1′-bis(diphenylphosphine)ferrocene]-dichloropalladium (1.0 g, 1.22mmol). The mixture was heated at 80° C. for 18 h. The reaction mixturewas cooled to RT and pardoned between EtOAc and H₂O. The organic layerwas washed successively with H₂O and brine, dried (Na₂SO₄) andconcentrated in vacuo. The resulting residue was purified by columnchromatography (silica gel, pentane:EtOAc 75:25) to provide the titlecompound as a white solid (4.6 g, 61%).

NMR δ_(H) (300 MHz, CDCl₃) 1.39 (s, 12H), 7.02 (m, 1H), 7.14-7.19 (m,1H), 7.20-7.26 (m, 1H), 7.38 (dd, J=2.4, 9.9, 1H) and 8.16 (s, 1H).

Reference Example 262-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol

To a solution of5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (1.33 g,4.91 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.74 mL, 5.40 mmol)in anhydrous THF (50 mL) was added a solution of n-BuLi (2.5 M inhexanes, 2.4 mL, 6.0 mmol) dropwise at −78° C. The reaction mixture wasstirred for 15 min, then a solution of benzaldehyde (0.65 mL, 6.29 mmol)in anhydrous THF (5 mL) was added rapidly. The mixture was stirred at−78° C. for 15 min, then allowed to warm to RT and partitioned betweenEtOAc and H₂O. The organic layer was isolated, washed with brine, thendried (Na₂SO₄) and concentrated in vacuo. The resultant residue waspurified by column chromatography to give the title compound as a yellowsolid (1.20 g, 66%).

[M+H]⁺ 377.0

Reference Example 275-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde

To a suspension of2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol(1.1 g, 2.9 mmol) in toluene (25 mL) was added p-toluenesulfonic acid(0.11 g, 0.58 mmol) and the resulting solution stirred at 120° C. for 24h. The reaction mixture was concentrated in vacuo to give5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine as a crudeyellow solid which was used without purification. To a suspension of5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine (2.9 mmol)in THF (9 mL), acetonitrile (9 mL) and H₂O (3 mL) were addedruthenium(III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g,5.80 mmol). The resulting solution was stirred at RT for 2 h, thenpartitioned between EtOAc and an aqueous solution of sodium thiosulfate.The aqueous layer was isolated and extracted with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedin vacuo. The resultant residue was purified by column chromatography togive the title compound as a yellow solid (0.34 g, 42%).

¹H NMR (400 MHz, CDCl₃): δ 3.83-3.88 (m, 4H), 4.06-4.15 (m, 2H), 4.72(m, 2H) and 9.95 (s, 1H).

Reference Example 285-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

To a solution of5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (57mg, 0.20 mmol) in 1,2-dichloroethane (2 mL) was addedhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (46mg, 0.22 mmol). The mixture was stirred at RT for 5 min before sodiumtriacetoxyborohydride (64 mg, 0.30 mmol) was added. The resultingsolution was stirred at RT for 1 h. The crude reaction mixture waspartitioned between DCM and brine. The organic layer was isolated, thendried (MgSO₄) and concentrated in vacuo. The resultant residue waspurified by column chromatography to give the title compound as a whitesolid (83 mg, 86%).

¹H NMR (400 MHz, CDCl₃): δ 1.45 (s, 9H), 1.55 (m, 2H), 2.61 (m, 2H),2.75-2.87 (m, 4H), 3.23 (m, 2H), 3.57 (s, 2H), 3.80 (t, J=4.8 Hz, 4H),3.91 (m, 2H) and 4.31 (m, 2H).

Reference Example 292-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-2,7-diaza-spiro[3.5]nonane-7-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acidtert-butyl ester hydrochloride in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a white solid (70 mg, 71%).

[M+H]⁺ 495.3

Reference Example 303-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a white solid (91 mg, 95%).

¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 1.90 (m, 2 μl), 1.93-2.00 (m,2H), 2.54 (bs, 2H), 2.74 (dd, J=10.6, 2.6 Hz, 2H), 3.79 (s, 2H), 3.82(m, 4H) and 4.12-4.43 (m, 6H).

Reference Example 312-(4-Azetidin-1-yl-piperidin-1-ylmethyl)-5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 4-azetidin-1-yl-piperidine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a cream solid (54 mg, 66%).

[M+H]⁺ 409.3

Reference Example 325-Chloro-2-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine inplace of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butylester. The title compound was obtained as a white solid (34 mg, 43%).

[M+H]⁺ 395.3

Reference Example 338-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-2,8-diaza-spiro[4.5]decane-2-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acidtert-butyl ester in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a white solid (81 mg, 80%).

[M+H]⁺ 509.3

Reference Example 345-Chloro-2-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using cis-2,6-dimethyl-piperazine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a pale yellow solid (32 mg, 42%).

[M+H]⁺ 383.3

Reference Example 352-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-2,7-diaza-spiro[3.5]nonane-7-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acidtert-butyl ester in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a white solid (46.4 mg, 72%).

¹H NMR (400 MHz, CDCl₃): δ 1.43 (s, 9H), 1.73 (t, J=5.3 Hz, 4H),3.08-3.35 (m, 4H), 3.27-3.37 (m, 4H), 3.78-3.84 (m, 4H), 3.90-3.95 (m,5H) and 4.07 (d, J=9.0 Hz, 2H).

Reference Example 365-Chloro-7-morpholin-4-O-2-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thiazolo[4,5-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 4-piperidin-4-yl-morpholine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a cream solid (28 mg, 80%).

¹H NMR (400 MHz, CDCl₃): δ 1.63 (q, J=12.3 Hz, 2H), 1.92 (d, J=12.3 Hz,2H), 2.24 (m, 1H), 2.34 (t, J=11.5 Hz, 2H), 2.60 (m, 4H), 3.04 (d,J=11.5 Hz, 2H), 3.76 (t, J=4.4 Hz, 4H), 3.81-3.86 (m, 4H) and 3.92-3.98(m, 6H).

Reference Example 372-Methyl-4-(trifluoromethanesulfonyloxy)thiazole-5-carboxylic acid ethylester

To a solution of 4-hydroxy-2-methylthiazole-5-carboxylic acid ethylester (1.87 g, 10 mmol) in DCM (50 mL) at −78° C. under an atmosphere ofN₂ was added triethylamine (2.08 mL, 15 mmol), followed by dropwiseaddition of trifluoromethanesulfonic anhydride (1.85 mL, 11 mmol). Theresulting mixture was stirred at −78° C. for 1 h then warmed to RT. Thesolvent was removed in vacuo and the resulting residue was purified bycolumn chromatography to give the title compound as a yellow oil (2.86g, 90%).

[M+H]⁺ 320.0

Reference Example 386-Benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione

To a solution of2-methyl-4-(trifluoromethanesulfonyloxy)thiazole-5-carboxylic acid ethylester (6.38 g, 20 mmol) in dioxane (80 mL) under an atmosphere of N₂ wasadded cesium carbonate (13.0 g, 40 mmol), benzylurea (3.3 g, 22 mmol),Xantphos (0.58 g, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0)(0.46 g, 0.5 mmol). The resulting mixture was stirred at 60° C. for 18h, cooled to RT, then poured onto water (500 mL) and stirred for 15 min.The resulting mixture was filtered, the filtrate collected and reducedin volume in vacuo to approximately one-third. The resultant precipitatewas collected by filtration, washed with ether and dried in vacuo togive the title compound as a white solid (3.9 g, 72%).

[M+H]⁺ 274.1

Reference Example 394-(5-Chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-2,2-dimethylpiperazine-1-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]-pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 2,2-dimethylpiperazine-1-carboxylic acidtert-butyl ester in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a yellow solid (100 mg, 38%).

[M+H]⁺ 483.2

Reference Example 405-Chloro-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 4-piperidin-4-ylmorpholine in place ofhexahydro-pyrrolo[3,4-e]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a yellow solid (220 mg, 39%).

[M+H]⁺ 439.2

Reference Example 415-Chloro-2-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine inplace of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butylester. The title compound was obtained as an orange solid (131 mg, 46%).

[M+H]⁺ 395.4

Reference Example 42 4-Azetidin-1-yl-piperidine

To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodiumtriacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resultingsolution was stirred at RT for 18 h. The reaction mixture waspartitioned between water and DCM and the layers separated. The organiclayer was extracted further with DCM and the combined aqueous layerswere concentrated in vacuo. The resultant white semi-solid was suspendedin DCM and a saturated aqueous solution of NaHCO₃ was added. The layerswere thoroughly mixed, the organic layer isolated and the aqueous layerfurther extracted with DCM. The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to give4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a whitesolid (2.0 g, 95%). BOC-deprotection of4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg,1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil(185 mg, 79%)

NMR δ_(H) (400 MHz, CDCl₃) 1.04-1.16 (m, 2H), 1.68 (d, J=12.8 Hz, 2H),1.98-2.08 (m, 3H), 2.55 (td, J=12.1, 2.6 Hz, 2H), 3.06 (dt, J=12.8, 3.6Hz, 2H) and 3.15 (t, J=6.9 Hz, 4H).

Reference Example 432-(4-Azetidin-1-ylpiperidin-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 4-azetidin-1-yl piperidine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a yellow solid (97 mg, 33%).

[M+H]⁺ 409.3 (³⁵Cl) and 411.3 (³⁷Cl)

Reference Example 445-Chloro-2-(4-cyclopropylmethylpiperazin-1-ylmethyl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 1-cyclopropylmethylpiperazine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as a yellow solid (170 mg, 58%).

[M+H]⁺ 409.5

Reference Example 45[1-(5-Chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-yl-methyl)-piperidin-4-yl]dimethylamine

Prepared according to the method used in the preparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using dimethylpiperidin-4-ylamine in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as an orange solid (244 mg, 40%).

[M+H]⁺ 397.2 (³⁵Cl) and 399.2 (³⁷Cl)

Reference Example 462-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-isobutyramide

To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) indichloromethane (150 mL) and methanol (150 mL) at 0° C. was addedhydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture wasstirred at room temperature for 1.5 hours and reduced in vacuo to yieldtert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

To a solution of tert-butyl-1-piperazinecarboxylate hydrochloride (17.9g) in water (200 mL) at room temperature was added sodium cyanide (3.94g). A solution of acetone (5.9 mL) in water (20 mL) was then addeddropwise and stirred at room temperature for 48 hours. The mixture waspartitioned between ethyl acetate and water. The combined organic layerswere washed with brine, separated, dried (MgSO₄) and reduced in vacuo toyield 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butylester (17.5 g).

To a solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester (960 mg) in methyl sulfoxide (20 mL) at 0° C. was addedpotassium carbonate (104 mg). Hydrogen peroxide (2.0 mL; 27.5 wt %solution in water) was then added dropwise. The resulting mixture washeated to 40° C. overnight. To the cooled mixture was added water andthe precipitated solid filtered and dried yielding4-(1-carbamoyl-2-methyl-ethyl)-piperazine-1-carboxylic acid tert-butylester (677 mg). The BOC-group was removed using HCl in ether understandard conditions to give 2-piperazine-1-yl-isobutyramidedi-hydrochloride (600 mg).

The title compounds was prepared according to the method used in thepreparation of5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester using 2-piperazin-1-yl-isobutyramide in place ofhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. Thetitle compound was obtained as an off-white solid (71 mg, 36%).

[M+H]⁺ 440.2

Reference Example 472-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholio-4-ylthiazolo[5,4-d]pyrimidine

To a solution of5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (308mg, 1.08 mmol) in DCE (8 mL) was added 4-azetidin-1-ylpiperidine (166mg, 1.19 mmol). The resulting mixture was stirred at RT for 10 min thensodium triacetoxyborohydride (297 mg, 1.40 mmol) was added and stirringwas continued for 18 h. The reaction mixture was loaded onto an Isolute®SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH andconcentrated in vacuo to give the title compound as an off-white solid(263 mg, 60%).

[M+H]⁺ 409.2

Reference Example 484-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazine-1-carboxylicacid tert-butyl ester

Prepared according to the method used in the preparation of2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidineusing piperazine-1-carboxylic acid tert-butyl ester in place of4-azetidin-1-ylpiperidine. The title compound was obtained as a whitesolid (129 mg, 81%).

[M+H]⁺ 455.2

5-Chloro-2-(4-cyclopropylpiperazin-1-ylmethyl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine

Prepared according to the method used in the preparation of2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidineusing 1-cyclopropylpiperazine in place of 4-azetidin-1-ylpiperidine. Thetitle compound was obtained as a white solid (117 mg, 56%).

[M+H]⁺ 395.5

Reference Example 502-[4-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide

Prepared according to the method used in the preparation of2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-c]pyrimidineusing 2-piperazin-1-ylisobutyramide in place of4-azetidin-1-ylpiperidine. The title compound was obtained as a whitesolid (70 mg, 46%).

[M+H]⁺ 440.3

Reference Example 51[1-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]dimethylamine

Prepared according to the method used in the preparation of2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidineusing dimethylpiperidin-4-ylamine in place of 4-azetidin-1-ylpiperidine.The title compound was obtained as a pale yellow solid (101 mg, 72%).

[M+H]⁺ 397.4

Reference Example 525-Chloro-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)-thiazolo[5,4-d]pyrimidine

Prepared according to the method used in the preparation of2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidineusing 4-piperidin-4-ylmorpholine in place of 4-azetidin-1-ylpiperidine.The title compound was obtained as a white solid (104 mg, 67%).

[M+H]⁺ 397.4

Example 15-(6-Fluoro-1H-indol-4-yl)-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine

This compound was produced using the Suzuki coupling Method B describedin Reference Example 2 above, followed by BOC-deprotection using TFA:DCM(1:1). The title compound was obtained as a pale yellow film (2.0 mg,16%).

[M+H]⁺ 480.2

¹H NMR (400 MHz, CH₃OH-d₄): δ 2.63 (dd, J=9.6, 5.6 Hz, 2H), 3.01 (d,J=9.6 Hz, 2H), 3.06 (m, 2H), 3.20 (dd, J=11.8, 4.3 Hz, 2H), 3.45-3.54(m, 2H), 3.89 (t, J=4.8 Hz, 4H), 4.07 (t, J=4.8 Hz, 4H), 4.18 (s, 2H),7.24 (dd, J=11.3, 2.4, 1H), 7.35 (d, J=3.2 Hz, 1H), 7.44 (dd, J=3.2, 1Hz, 1H) and 7.88 (dd, J=11.3, 2.4 Hz, 1H).

Example 25-(6-Fluoro-1H-indol-4-yl)-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3. The title compound was obtained as an off-whitesolid (2.0 mg, 16%).

[M+H]⁺ 480.13

¹H NMR (400 MHz, CD₃OD): δ 2.57 (dd, J=9.6, 5.3 Hz, 2H), 2.98 (d, J=9.6Hz, 2H), 2.99-3.06 (m, 2H), 3.13 (dd, J=11.7, 5.3 Hz, 2H), 3.57 (dd,J=11.7, 7.2 Hz, 2H), 3.87 (t, J=4.7 Hz, 4H), 4.06 (s, 2H), 4.45 (t,J=4.7 Hz, 4H), 7.22 (dd, J=10.6, 2.4 Hz, 1H), 7.30 (dd, J=3.2, 0.9 Hz,1H), 7.34 (d, J=3.2 Hz, 1H) and 7.77 (dd, J=10.6, 2.4 Hz, 1H).

Example 32-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3. The title compound was obtained as a off-whitesolid (15 mg, 29%).

[M+H]⁺ 476.3

¹H NMR (400 MHz, CDCl₃): δδ 1.74-1.79 (m, 4H), 2.79 (t, J=5.3 Hz, 4H),3.21 (s, 4H), 3.88-3.94 (m, 4H), 3.99 (s, 2H), 4.45 (m, 4H), 7.30 (t,J=7.7 Hz, 1H), 7.33 (t, J=2.7 Hz, 1H), 7.49-7.53 (m, 2H), 8.18 (dd,J=7.7, 1.0 Hz, 1H) and 8.30 (bs, 1H).

Example 42-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3. The title compound was obtained as a pale greysolid (20 mg, 58%).

[M+H]⁺ 494.3

¹H NMR (400 MHz, CDCl₃): δ 1.77 (t, J=5.4 Hz, 4H), 2.79 (t, J=5.4 Hz,4H), 3.21 (s, 4H), 3.90 (t, J=4.6 Hz, 4H), 3.99 (s, 2H), 4.45 (t, J=4.6Hz, 4H), 7.18 (dd, J=8.8, 2.5 Hz, 1H), 7.31 (t, J=2.5 Hz, 1H), 7.51 (m,1H), 7.95 (m, 1H) and 8.27 (bs, 1H).

Example 52-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3 and TBDMS-deprotection using TBAF:THF (1:10)according to Reference Example 4. The title compound was obtained as agrey solid (49 mg, 55%).

[M+H]⁺ 494.3

¹H NMR (400 MHz, CDCl₃): δ 1.75 (t, J=5.3 Hz, 4H), 2.78 (t, J=5.3 Hz,4H), 3.20 (s, 4H), 3.86 (m, 4H), 4.00 (s, 2H), 4.42 (m, 4H), 6.93 (bs,1H), 7.04 (dd, J=11.0, 8.8 Hz, 1H), 7.28 (m, 1H), 7.37 (dd, J=8.8, 3.8Hz, 1H) and 8.32 (bs, 1H).

Example 62-(3,8-Diaza-bicyclo[3.2.1]oct-3-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3. The title compound was obtained as a white solid(3.0 mg, 7%).

[M+H]⁺ 462.2

¹H NMR (400 MHz, CD₃OD): δ 2.03-2.08 (m, 2H), 2.27-2.33 (m, 2H), 2.73(d, J=12.5 Hz, 2H), 3.03 (dd, J=12.5, 2.7 Hz, 2H), 3.83-3.88 (m, 4H),4.02 (m, 4H), 4.45 (m, 4H), 7.20 (t, J=7.8 Hz, 1H), 7.27 (dd, J=3.2, 0.9Hz, 1H), 7.35 (d, J=3.2 Hz, 1H), 7.52 (apparent dt, J=7.8, 0.9 Hz, 1H)and 7.98 (dd, J=7.8, 0.9 Hz, 1H).

Example 72-(4-Azetidin-1-yl-piperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B), followed by BOC-deprotection using TFA:DCM (1:2) accordingto Reference Example 3. The title compound was obtained as a off-whitesolid (15 mg, 24%).

[M+H]⁺ 490.3

¹H NMR (400 MHz, CD₃OD): δ 1.15-1.29 (m, 2H), 1.67 (d, J=12.1 Hz, 2H),1.92-2.00 (m, 2H), 2.23 (t, J=11.30 Hz, 2H), 2.86 (d, J=11.0 Hz, 2H),3.21 (m, 3H), 3.80 (m, 4H), 3.88 (s, 2H), 4.34 (m, 4H), 7.19 (apparentt, J=7.8 Hz, 1H), 7.33 (s, 1H), 7.45 (t, J=2.7 Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 8.09 (d, J=7.8 Hz, 1H) and 11.25 (bs, 1H).

Example 82-[(S)-1-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(scheme B).

The title compound was obtained as a pale yellow solid (34 mg, 83%).

[M+H]⁺ 476.2

¹H NMR (400 MHz, CDCl₃): δ 1.46 (m, 1H), 1.60 (m, 1H), 1.67-1.93 (m,3H), 2.13-2.29 (m, 2H), 2.41 (m, 1H), 2.55 (m, 1H), 2.96 (d, J=10.9 Hz,1H), 3.01-3.14 (m, 3H), 3.86-3.94 (m, 6H), 4.44 (t, J=4.6 Hz, 4H),7.28-7.33 (m, 2H), 7.47-7.52 (m, 2H), 8.17 (dd, J=7.5, 1.0 Hz, 1H) and8.29 (bs, 1H).

Example 92-(3,5-Dimethyl-piperazin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine

Prepared by using the Suzuki coupling Method of Reference Example 2(scheme B). The title compound was obtained as a beige solid (24 mg,62%).

[M+H]⁺ 464.3

¹H NMR (400 MHz, CDCl₃): δ 1.05 (d, J=6.4 Hz, 6H), 1.86 (t, J=10.5 Hz,2H), 2.86-2.92 (m, 2H), 2.96-3.06 (m, 2H), 3.84 (s, 2H), 3.89 (t, J=4.6Hz, 4H), 4.44 (t, J=4.6 Hz, 4H), 7.26-7.33 (m, 2H), 7.47-7.52 (m, 2H),8.17 (dd, J=7.7, 0.9 Hz, 1H) and 8.29 (bs, 1H).

Example 102-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidineformate

Prepared using the Suzuki coupling Method B of Reference Example 2(scheme A), followed by BOC-deprotection using TFA:DCM (2:3) accordingto Reference Example 3. The formate salt of the title compound wasobtained as a cream solid (2.6 mg, 12%).

[M+H]⁺ 494.2

¹H NMR (400 MHz, CD₃OD): δ 2.02 (t, J=5.6 Hz, 4H), 3.08-3.14 (m, 4H),3.37 (s, 4H), 3.89 (t, J=4.7 Hz, 4H), 4.07 (t, J=4.7 Hz, 4H), 4.19 (s,2H), 7.23 (ddd, J=10.0, 2.4, 0.9 Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.42(dd, J=3.2, 0.9 Hz, 1H), 7.86 (dd, J=10.0, 2.4 Hz, 1H) and 8.54 (bs,1H).

Example 115-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thiazolo[4,5-d]pyrimidine

Prepared by using the Suzuki coupling Method B of Reference Example 2(Scheme A). The title compound was obtained as tan glass (10 mg, 20%).

[M+H]⁺ 520.2

¹H NMR (400 MHz, DMSO-d₆): δ 1.41-1.54 (m, 2H), 1.81 (d, J=12.3 Hz, 2H),2.11-2.22 (m, 1H), 2.23-2.36 (m, 2H), 2.44-2.49 (m, 4H), 3.02 (d, J=11.2Hz, 2H), 3.57 (t, J=4.3 Hz, 4H), 3.82 (t, J=4.6 Hz, 4H), 3.98 (t, J=4.6Hz, 4H), 4.01 (s, 2H), 7.21 (t, J=7.8 Hz, 1H), 7.42-7.48 (m, 2H), 7.54(d, J=8.0 Hz, 1H), 8.14 (dd, J=7.8, 1.0 Hz, 1H) and 11.25 (bs, 1H).

Example 122-(3,3-Dimethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared using Suzuki coupling method C, followed by TBS andBOC-deprotection. The title compound was obtained as a yellow solid (13mg, 22%).

[M+H]⁺ 482.1

¹H NMR (400 MHz, DMSO): δ 1.16 (s, 6H), 2.31-2.38 (m, 2H), 2.57 (m, 2H),2.87-2.94 (m, 2H), 3.74-3.80 (m, 4H), 3.92 (m, 4H), 3.98 (s, 2H), 6.73(m, 1H), 7.07 (dd, J=11.4, 8.8 Hz, 1H), 7.45 (m, 1H), 7.48 (dd, J=8.9,4.0 Hz, 1H) and 11.28 (s, 1H).

Example 135-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-O-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine

Prepared by using Suzuki coupling method G. The title compound wasobtained as a pale yellow solid (101 mg, 76%).

[M+H]⁺ 538.1

¹H NMR (400 MHz, DMSO): δ 1.42-1.55 (m, 2H), 1.80 (d, J=11.8 Hz, 2H),2.17 (tt, J=11.1, 3.6 Hz, 1H), 2.22-2.31 (m, 2H), 2.44-2.49 (m, 4H),3.02 (d, J=11.6 Hz, 2H), 3.58 (m, 4H), 3.77 (m, 4H), 3.92 (m, 4H), 4.01(s, 2H), 6.73 (m, 1H), 7.02 (dd, J=11.0, 8.9 Hz, 1H), 7.43-7.50 (m, 2H)and 11.27 (bs, 1H).

Example 145-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolopyrimidine

Prepared by using Suzuki coupling method F. The title compound wasobtained as an off-white solid (55 mg, 43%).

[M+H]⁺ 520.2

¹H NMR (400 MHz, CDCl₃): δ 1.63 (m, 2H), 1.91 (d, J=11.8 Hz, 2H),2.17-2.28 (m, 1H), 2.29-2.39 (m, 2H), 2.53-2.65 (m, 4H), 3.09 (d, J=11.1Hz, 2H), 3.72-3.78 (m, 4H), 3.89-3.95 (m, 4H), 4.00 (s, 2H), 4.03-4.08(m, 4H), 7.27-7.35 (m, 2H), 7.51 (d, J=8.2 Hz, 1H), 7.68 (m, 1H), 8.32(bs, 1H) and 8.36 (m, 1H).

Example 155-(5-Fluoro-1H-indol-4-yl)-2-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared by using Suzuki coupling method G. The title compound wasobtained as an orange solid (41 mg, 25%).

[M+H]⁺ 494.1

¹H NMR (400 MHz, CDCl₃): δ 1.38-1.51 (m, 1H), 1.71-1.93 (m, 3H),2.15-2.28 (m, 3H), 2.37-2.46 (m, 1H), 2.60 (td, J=10.9, 3.0 Hz, 1H),2.95-3.16 (m, 4H), 3.84-3.90 (m, 4H), 4.00-4.05 (m, 4H), 4.08 (d, J=5.5Hz, 2H), 7.04 (dd, J=10.9, 8.7 Hz, 1H), 7.09-7.11 (m, 1H), 7.28 (t,J=2.9 Hz, 1H), 7.35-7.40 (m, 1H) and 8.30 (bs, 1H).

Example 162-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared by using Suzuki coupling method G. The title compound wasobtained as a yellow solid (8 mg, 7%).

[M+H]⁺ 508.16

¹H NMR (400 MHz, CDCl₃): δ 1.37-1.49 (m, 2H), 1.71-1.79 (m, 2H),2.00-2.11 (m, 3H), 2.37 (td, J=11.5, 2.3 Hz, 2H), 2.94-3.01 (m, 2H),3.20 (t, J=6.9 Hz, 4H), 3.87 (m, 4H), 4.01 (m, 6H), 7.04 (dd, J=11.2,8.9 Hz, 1H), 7.09 (m, 1H), 7.27 (m, 1H), 7.34-7.39 (m, 1H) and 8.31 (bs,1H).

Example 172-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared by using Suzuki coupling method E. The title compound wasobtained as a yellow solid (48 mg, 52%).

[M+H]⁺ 490.1

¹H NMR (400 MHz, CDCl₃): δ 1.37-1.49 (m, 2H), 1.71-1.79 (m, 2H),2.01-2.12 (m, 3H), 2.37 (td, J=11.3, 2.3 Hz, 2H), 2.94-3.01 (m, 2H),3.16-3.24 (m, 4H), 3.89-3.94 (m, 4H), 4.00 (s, 2H), 4.03-4.07 (m, 4H),7.28-7.34 (m, 2H), 7.51 (bd, J=8.0 Hz, 1H), 7.69 (m, 1H), 8.31 (bs, 1H)and 8.36 (m, 1H).

Example 182-(4-Cyclopropylmethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine

Prepared by using Suzuki coupling method G, followed byTBS-deprotection. The title compound was obtained as a yellow solid (74mg, 35%).

[M+H]⁺ 508.1

¹H NMR (400 MHz, CDCl₃): δ 0.14 (q, J=5.0 Hz, 2H), 0.51-0.58 (m, 2H),0.84-0.95 (m, 1H), 2.33 (d, J=5.7 Hz, 2H), 2.58-2.84 (m, 8H), 3.84-3.90(m, 4H), 4.00-4.05 (m, 6H), 7.04 (dd, J=11.2, 8.7 Hz, 1H), 7.10 (m, 1H),7.28 (m, 1H), 7.38 (m, 1H) and 8.31 (bs, 1H).

Example 19{1-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine

Prepared by using Suzuki coupling method D. The title compound wasobtained as an orange solid (67 mg, 45%).

[M+H]⁺ 496.1

¹H NMR (400 MHz, CDCl₃): δ 1.56-1.71 (m, 4H), 1.85-1.93 (m, 2H),2.13-2.22 (m, 1H), 2.32 (s, 6H), 3.04-3.12 (m, 2H), 3.87 (m, 4H), 4.02(m, 6H), 7.04 (dd, J=11.1, 8.9 Hz, 1H), 7.10 (m, 1H), 7.28 (m, 1H), 7.38(ddd, J=8.7, 3.9, 0.9 Hz, 1H) and 8.31 (bs, 1H).

Example 20{1-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine

Prepared by using Suzuki coupling method E. The title compound wasobtained as an orange solid (123 mg, 70%).

[M+H]⁺ 478.1

¹H NMR (400 MHz, CDCl₃): δ 1.58-1.72 (m, 4H), 1.86-1.93 (m, 2H),2.15-2.24 (m, 1H), 2.33 (s, 6H), 3.04-3.12 (m, 2H), 3.89-3.95 (m, 4H),4.01 (s, 2H), 4.03-4.09 (m, 4H), 7.28-7.34 (m, 2H), 7.52 (m, 1H), 7.68(m, 1H), 8.32 (bs, 1H) and 8.36 (dd, J=7.4, 0.9 Hz, 1H).

Example 212-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl]-piperazin-1-yl}-isobutyramide

Prepared by using Suzuki coupling method G. The title compound wasobtained as an orange solid (7 mg, 12%).

[M+H]⁺ 539.3

¹H NMR (400 MHz, DMSO): δ 1.10 (s, 6H), 2.49-2.54 (m, 4H, hidden),2.66-2.71 (m, 4H), 3.76-3.79 (m, 4H), 3.90-3.93 (m, 4H), 4.03 (s, 2H),6.72 (m, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.02 (dd, J=11.5, 9.0 Hz, 1H),7.10 (d, J=2.5 Hz, 1H), 7.45 (t, J=2.7 Hz, 1H), 7.48 (ddd, J=8.5, 4.1,1.0 Hz, 1H) and 11.27 (s, 1H).

Example 222-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine

Prepared by using Suzuki coupling method G. The title compound wasobtained as an off-white solid (69 mg, 43%).

[M+H]⁺ 508.2

¹H NMR (400 MHz, CDCl₃): δ 1.35-1.45 (m, 2H), 1.67-1.74 (m, 2H),2.00-2.10 (m, 3H), 2.28 (td, J=11.1, 2.5 Hz, 2H), 2.95 (dt, J=12.1, 3.8Hz, 2H), 3.19 (t, J=7.0 Hz, 4H), 3.84-3.87 (m, 6H), 4.39-4.44 (m, 4H),6.92-6.94 (m, 1H), 7.04 (dd, J=11.1, 8.9 Hz, 1H), 7.29 (t, J=2.9 Hz,1H), 7.37 (dd, J=8.9, 3.8 Hz, 1H) and 8.34 (bs, 1H).

Example 235-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-piperazin-1-ylmethylthiazolo[5,4-d]pyrimidine

Prepared by using Suzuki coupling method G, followed byBOC-deprotection. The title compound was obtained as a white solid (46mg, 37%).

[M+H]⁺ 454.1

¹H NMR (400 MHz, CDCl₃): δ 2.59-2.68 (m, 4H), 2.96 (t, J=4.9 Hz, 4H),3.84-3.88 (m, 6H), 4.39-4.43 (m, 4H), 6.91-6.94 (m, 1H), 7.04 (dd,J=11.1, 8.6 Hz, 1H), 7.29 (t, J=3.2 Hz, 1H), 7.37 (ddd, J=8.9, 3.5, 0.9Hz, 1H) and 8.34 (bs, 1H).

Example 242-(4-Cyclopropylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine

Prepared by using Suzuki coupling method G. The title compound wasobtained as a white solid (63 mg, 46%).

[M+H]⁺ 494.1

¹H NMR (400 MHz, CDCl₃): δ 0.38-0.49 (m, 4H), 1.64-1.70 (m, 1H),2.61-2.75 (m, 8H), 3.86 (t, J=5.1 Hz, 4H), 3.88 (s, 2H), 4.39-4.44 (m,4H), 6.92-6.94 (m, 1H), 7.04 (dd, J=11.1, 8.6 Hz, 1H), 7.29 (t, J=3.2Hz, 1H), 7.37 (ddd, J=8.9, 3.5, 0.9 Hz, 1H) and 8.31 (bs, 1H).

Example 252-{4-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide

Prepared by using Suzuki coupling method F. The title compound wasobtained as an off-white solid (83 mg, 47%).

[M+H]⁺ 521.2

¹H NMR (400 MHz, DMSO): δ 1.10 (s, 6H), 2.47-2.52 (m, 4H), 2.62-2.67 (m,4H), 3.81 (t, J=4.5 Hz, 4H), 3.92 (s, 2H), 4.33-4.38 (m, 4H), 6.97 (d,J=2.8 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.34-7.36(m, 1H), 7.46 (t, J=2.8 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.4Hz, 1H) and 11.31 (bs, 1H).

Example 262-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide

Prepared by using Suzuki coupling method G. The title compound wasobtained as an off-white solid (15 mg, 17%).

[M+H]⁺ 539.3

¹H NMR (400 MHz, DMSO): δ 1.09 (s, 6H), 2.46-2.51 (m, 4H), 2.60-2.67 (m,4H), 3.76 (t, J=5.1 Hz, 4H), 3.93 (s, 2H), 4.27-4.32 (m, 4H), 6.69-6.71(m, 1H), 6.97 (d, J=3.5 Hz, 1H), 7.00 (dd, J=11.1, 8.9 Hz, 1H), 7.08 (d,J=3.5 Hz, 1H), 7.44-7.49 (m, 2H), and 11.31 (bs, 1H).

Example 27{1-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine

Prepared by using Suzuki coupling method B. The title compound wasobtained as a tan solid (75 mg, 62%).

[M+H]⁺ 478.2

¹H NMR (400 MHz, CDCl₃): δ 1.59-1.71 (m, 2H), 1.87 (d, J=12.6 Hz, 2H),2.25 (dt, J=12.2, 1.8 Hz, 3H), 2.35 (s, 6H), 3.07 (d, J=12.0 Hz, 2H),3.87 (s, 2H), 3.90 (t, J=4.3 Hz, 4H), 4.43-4.46 (m, 4H), 7.30 (t, J=7.5Hz, 1H), 7.34 (t, J=2.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.51-7.53 (m,1H), 8.18 (d, J=7.1 Hz, 1H) and 8.30 (bs, 1H).

Example 285-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine

Prepared by using Suzuki coupling method B. The title compound wasobtained as a tan solid (38 mg, 64%).

[M+H]⁺ 520.2

¹H NMR (400 MHz, CDCl₃): δ 1.63 (qd, J=11.3, 3.7 Hz, 2H), 1.87 (d,J=11.3 Hz, 2H), 2.18-2.29 (m, 3H), 2.55-2.59 (m, 4H), 3.07 (d, J=11.9Hz, 2H), 3.72-3.76 (m, 4 μl), 3.86 (s, 2H), 3.90 (t, J=5.1 Hz, 4H),4.43-4.47 (m, 4H), 7.30 (t, J=8.1 Hz, 1H), 7.34 (t, J=2.9 Hz, 1H),7.49-7.53 (m, 2H), 8.18 (d, J=7.6 Hz, 1H) and 8.29 (bs, 1H).

Example 295-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine

Prepared by using Suzuki coupling method C. The title compound wasobtained as a tan solid (27 mg, 45%).

[M+H]⁺ 538.2

¹H NMR (400 MHz, CDCl₃): δ 1.63 (qd, J=11.3, 3.7 Hz, 2H), 1.87 (d,J=11.3 Hz, 2H), 2.18-2.29 (m, 3H), 2.55-2.59 (m, 4H), 3.07 (d, J=11.9Hz, 2H), 3.72-3.76 (m, 4H), 3.84-3.87 (m, 6H), 4.40 (m, 4H), 6.92-6.94(m, 1H), 7.05 (dd, J=11.0, 8.5 Hz, 1H), 7.29 (t, J=2.0 Hz, 1H), 7.38(dd, J=8.4, 4.2 Hz, 1H) and 8.24 (bs, 1H).

Example 30 Biological Testing

Compounds of the invention, prepared as described in the precedingExamples, were submitted to the following biological assay:

PI3K Biochemical Screening

Compound inhibition of PI3K was determined in a radiometric assay usingpurified, recombinant enzyme and ATP at a concentration of 1 uM. Allcompounds were serially diluted in 100% DMSO. The kinase reaction wasincubated for 1 hour at room temperature, and the reaction wasterminated by the addition of PBS. IC₅₀ values were subsequentlydetermined using sigmoidal dose-response curve fit (variable slope). Allof the compounds tested had an IC₅₀ against PI3K of 50 μM or less.Typically the IC₅₀ against the p110δ isoform of PI3K was less than 500nM.

Example 31 Tablet Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention were manufactured as follows:

Composition for 10,000 tabletsCompound of the invention (250 g)

Lactose (800 g)

Corn starch (415 g)Talc powder (30 g)Magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch weremixed. The mixture was then forced through a sieve 0.5 mm mesh size.Corn starch (10 g) is suspended in warm water (90 ml). The resultingpaste was used to granulate the powder. The granulate was dried andbroken up into small fragments on a sieve of 1.4 mm mesh size. Theremaining quantity of starch, talc and magnesium was added, carefullymixed and processed into tablets.

Example 32 Injectable Formulation

Compound of the invention 200 mg Hydrochloric Acid Solution 0.1M or 4.0to 7.0 Sodium Hydroxide Solution 0.1M q.s. to pH Sterile water q.s. to10 ml

The compound of the invention was dissolved in most of the water(35°-40° C.) and the pH adjusted to between 4.0 and 7.0 with thehydrochloric acid or the sodium hydroxide as appropriate. The batch wasthen made up to volume with water and filtered through a sterilemicropore filter into a sterile 10 ml amber glass vial (type 1) andsealed with sterile closures and overseals.

Example 33 Intramuscular Injection

Compound of the invention 200 mg Benzyl Alcohol 0.10 g Glycofurol 751.45 g Water for injection q.s to 3.00 ml

The compound of the invention was dissolved in the glycofurol. Thebenzyl alcohol was then added and dissolved, and water added to 3 ml.The mixture was then filtered through a sterile micropore filter andsealed in sterile 3 ml glass vials (type 1).

Example 34 Syrup Formulation

Compound of invention 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 gSodium benzoate 0.005 g Flavour 0.0125 ml Purified Water q.s. to 5.00 ml

The compound of the invention was dissolved in a mixture of the glyceroland most of the purified water. An aqueous solution of the sodiumbenzoate was then added to the solution, followed by addition of thesorbital solution and finally the flavour. The volume was made up withpurified water and mixed well.

1. A compound which is a thiazolopyrimidine of formula (I):

wherein W represents a thiazole ring; R¹ and R² form, together with theN atom to which they are attached, a group of the following formula(IIa):

in which A is selected from: (a) a 4- to 7-membered saturatedN-containing heterocyclic ring which includes 0 or 1 additionalheteroatoms selected from N, S and O, the ring being unsubstituted orsubstituted; (b) a 4- to 7-membered saturated N-containing heterocyclicring which includes 0 or 1 additional heteroatoms selected from N, S andO, the ring being fused to a second ring selected from a 4- to7-membered saturated N-containing heterocyclic ring as defined above, a5- to 12-membered unsaturated heterocyclic ring, a 5- to 7-memberedsaturated O-containing heterocyclic ring, a 3- to 12-membered saturatedcarbocyclic ring and an unsaturated 5- to 12-membered carbocyclic ringto form a heteropolycyclic ring system, the heteropolycyclic ring systembeing unsubstituted or substituted; (c) a 4- to 7-membered saturatedN-containing heterocyclic ring which includes 0 or 1 additionalheteroatoms selected from N, S and O and which further comprises,linking two constituent atoms of the ring, a bridgehead group selectedfrom (CR′₂)_(n)— and (CR′₂)_(r)—O—(CR′₂)_(s)— wherein each R′ isindependently H or C₁-C₆ alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0or 1, the remaining ring positions being unsubstituted or substituted;and (d) a group of formula (IIb):

 wherein ring B is a 4- to 7-membered saturated N-containingheterocyclic ring which includes 0 or 1 additional heteroatoms selectedfrom N, S and O and ring B′ is a 3- to 12-membered saturated carbocyclicring, a 5- to 7-membered saturated O-containing heterocyclic ring or a4- to 7-membered saturated N-containing heterocyclic ring as definedabove, each of B and B′ being unsubstituted or substituted; or one of R¹and R² is C₁-C₆ alkyl and the other of R¹ and R² is selected from a 3-to 12-membered saturated carbocyclic group which is unsubstituted orsubstituted, a 5- to 12-membered unsaturated carbocyclic group which isunsubstituted or substituted, a 5- to 12-membered unsaturatedheterocyclic group which is unsubstituted or substituted, a 4- to12-membered saturated heterocyclic group which is unsubstituted orsubstituted and a C₁-C₆ alkyl group which is substituted by a groupselected from a 3- to 12-membered saturated carbocyclic group which isunsubstituted or substituted, a 5- to 12-membered unsaturatedcarbocyclic group which is unsubstituted or substituted, a 5- to12-membered unsaturated heterocyclic group which is unsubstituted orsubstituted and a 4- to 12-membered saturated heterocyclic group whichis unsubstituted or substituted; m is 0, 1 or 2; R³ is H or C₁-C₆ alkyl;and R⁴ is an indole group which is unsubstituted or substituted; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein the thiazolopyrimidine is of formula (Ia):

wherein R¹, R², R³, R⁴ and m are as defined in claim
 1. 3. A compoundaccording to claim 1 wherein the thiazolopyrimidine is of formula (Ib):

wherein R¹, R², R³, R⁴ and m are as defined in claim
 1. 4. A compoundaccording to claim 1 wherein R⁴ is an indole group which isunsubstituted or substituted by a group selected from CN, halo,—C(O)NR₂, halo(C₁-C₆)alkyl, —SO₂R, —SO₂NR₂, and a 5-membered heteroarylgroup containing 1, 2, 3 or 4 heteroatoms selected from O, N and S,wherein R is H or C₁-C₆ alkyl.
 5. A compound according to claim 1selected from:5-(6-Fluoro-1H-indol-4-yl)-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine;5-(6-Fluoro-1H-indol-4-yl)-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(3,8-Diaza-bicyclo[3.2.1]oct-3-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(4-Azetidin-1-yl-piperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-[(S)-1-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(3,5-Dimethyl-piperazin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine;2-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-5-(6-fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidineformate;5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thiazolo[4,5-d]pyrimidine;2-(3,3-Dimethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine;5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine;5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine;5-(5-Fluoro-1H-indol-4-yl)-2-[(S)-1-(hexahydro-pyrrolo[1,2-c]pyrazin-2-yl)methyl]-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine;2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-a]pyrimidine;2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine;2-(4-Cyclopropylmethylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidine;{1-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine;{1-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine;2-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-thiazoloylmethyl]-piperazin-1-yl}-isobutyramide;2-(4-Azetidin-1-ylpiperidin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine;5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-piperazin-1-ylmethylthiazolo[5,4-d]pyrimidine;2-(4-Cyclopropylpiperazin-1-ylmethyl)-5-(5-fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine;2-{4-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide;2-{4-[5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide;{1-[5-(1H-Indol-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-4-yl}dimethylamine;5-(1H-Indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine;and5-(5-Fluoro-1H-indol-4-yl)-7-morpholin-4-yl-2-(4-morpholin-4-ylpiperidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine;and the pharmaceutically acceptable salts thereof.
 6. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier ordiluent and, as an active ingredient, a compound according to claim 1.7-10. (canceled)
 11. A method of treating a disease or disorder arisingfrom abnormal cell growth, function or behaviour associated with P13kinase selected from cancer, immune disorders, cardiovascular disease,viral infection, inflammation, metabolism/endocrine function disordersand neurological disorders, which method comprises administering to apatient in need thereof a compound according to claim
 1. 12. (canceled)13. A compound according to claim 1 wherein the compound is 2-fold ormore selective for the p110δ (delta) isoform over the p110α (alpha),p110β (beta), and p110γ (gamma) isoforms.
 14. A compound according toclaim 1 wherein R³ is H and m is
 1. 15. A compound according to claim 1wherein the 4- to 7-membered saturated N-containing heterocyclic ring isselected from structures (i)-(ix):


16. A compound according to claim 1 wherein the 4- to 7-memberedsaturated N-containing heterocyclic ring is selected from structures(a)-(f):


17. A compound according to claim 1 wherein the 4- to 7-memberedsaturated N-containing heterocyclic ring is selected from structures(a′)-(f′):


18. A compound according to claim 1 wherein the 4- to 7-memberedsaturated N-containing heterocyclic ring is selected from structures(i′)-(x′):


19. A compound according to claim 4 wherein the indole group isindol-4-yl.
 20. A compound according to claim 19 wherein the indol-4-ylis unsubstituted or substituted with one or more fluorine.